Publications by authors named "Cristoforo Scavone"

85 Publications

The Janus face of ouabain in Na /K -ATPase and calcium signalling in neurons.

Br J Pharmacol 2021 Feb 28. Epub 2021 Feb 28.

Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Na /K -ATPase, a transmembrane protein essential for maintaining the electrochemical gradient across the plasma membrane, acts as a receptor for cardiotonic steroids such as ouabain. Cardiotonic steroids binding to Na /K -ATPase triggers signalling pathways or inhibits Na /K -ATPas activity in a concentration-dependent manner, resulting in a modulation of Ca levels, which are essential for homeostasis in neurons. However, most of the pharmacological strategies for avoiding neuronal death do not target Na /K -ATPase activity due to its complexity and the poor understanding of the mechanisms involved in Na /K -ATPase modulation. The present review aims to discuss two points regarding the interplay between Na /K -ATPase and Ca signalling in the brain. One, Na /K -ATPase impairment causing illness and neuronal death due to Ca signalling and two, benefits to the brain by modulating Na /K -ATPase activity. These interactions play an essential role in neuronal cell fate determination and are relevant to find new targets for the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1111/bph.15419DOI Listing
February 2021

Inverse sex-based expression profiles of PTEN and Klotho in mice.

Sci Rep 2020 11 19;10(1):20189. Epub 2020 Nov 19.

Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences 1, University of São Paulo, Avenida Professor Lineu Prestes, 1524, São Paulo, 05508-000, Brazil.

Sex differences are considered predictive factors in the development of several neurological diseases, which are also known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis. Here, under physiological conditions, we show important sex differences in the underlying balancing mechanisms that lead to similar AKT activity levels and autophagy and apoptosis processes in the two sexes. We demonstrate inverse sex-based expression of PTEN and Klotho, two important proteins that are known to negatively regulate the AKT pathway, and inverse sex-dependent levels of mTOR and FoxO3a activity. Taken together, our findings indicate that inverse sex-based regulation may be one of the underlying balancing mechanisms that differ between the sexes and a possible cause of sex-based autophagic and apoptotic responses to triggering situations that can lead to a sex-based predisposition to some neurological diseases.
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http://dx.doi.org/10.1038/s41598-020-77217-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677532PMC
November 2020

Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway.

IBRO Rep 2020 Dec 1;9:218-223. Epub 2020 Sep 1.

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, 05508-900, Brazil.

Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by intracellular inclusions named Lewy bodies (LB), and alpha-synuclein (asyn) is the major component of these protein aggregates. The precise physiological and pathological roles of asyn are not fully understood. Nevertheless, asyn present in LB is ubiquitinated but fails to reach the 26S proteasome. The mutation A30 P is related to an aggressive and early-onset form of PD. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase, and it interacts and ubiquitinates the asyn in atypical chains (lysine K6, K27, K29, and K33). Methods: Here, we investigated the role of TRAF6 interaction with asyn and the involvement of nuclear factor κB (NF-κB), a key transcription factor in pro-inflammatory signaling pathway activation.

Results And Conclusion: We demonstrated that TRAF6 binds to both WT and the mutant form A30 P asyn in an SH-SY5Y cell model. Additionally, the interaction between TRAF6 and WT asyn induced an increase in the activation of NF-κB, leading to changes in and levels and culminating in reduced cell viability. Interestingly, the activation of NF-κB and gene regulation were not found in A30 P asyn. These data point to a novel role of TRAF6 in the pathophysiology of PD.
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http://dx.doi.org/10.1016/j.ibror.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498709PMC
December 2020

21-Benzylidene digoxin decreases proliferation by inhibiting the EGFR/ERK signaling pathway and induces apoptosis in HeLa cells.

Steroids 2020 03 6;155:108551. Epub 2019 Dec 6.

Laboratório de Bioquímica Celular, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil. Electronic address:

Cardiotonic steroids (CTS) are agents traditionally known for their capacity to bind to the Na,K-ATPase (NKA), affecting the ion transport and the contraction of the heart. Natural CTS have been shown to also have effects on cell signaling pathways. With the goal of developing a new CTS derivative, we synthesized a new digoxin derivative, 21-benzylidene digoxin (21-BD). Previously, we have shown that this compound binds to NKA and has cytotoxic actions on cancer, but not on normal cells. Here, we further studied the mechanisms of actions of 21-BD. Working with HeLa cells, we found that 21-BD decreases the basal, as well as the insulin stimulated proliferation. 21-BD reduces phosphorylation of the epidermal growth factor receptor (EGFR) and extracellular-regulated kinase (ERK), which are involved in pathways that stimulate cell proliferation. In addition, 21-BD promotes apoptosis, which is mediated by the translocation of Bax from the cytosol to mitochondria and the release of mitochondrial cytochrome c to the cytosol. 21-BD also activated caspases-8, -9 and -3, and induced the cleavage of poly (ADP-ribose) polymerase-1 (PARP-1). Altogether, these results show that the new compound that we have synthesized exerts cytotoxic actions on HeLa cells by inhibition of cell proliferation and the activation of both the extrinsic and intrinsic apoptotic pathways. These results support the relevance of the cardiotonic steroid scaffold as modulators of cell signaling pathways and potential agents for their use in cancer.
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http://dx.doi.org/10.1016/j.steroids.2019.108551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028499PMC
March 2020

Insulin and Autophagy in Neurodegeneration.

Front Neurosci 2019 22;13:491. Epub 2019 May 22.

Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Crosstalk in the pathophysiological processes underpinning metabolic diseases and neurodegenerative disorders have been the subject of extensive investigation, in which insulin signaling and autophagy impairment demonstrate to be a common factor in both conditions. Although it is still somewhat conflicting, pharmacological and genetic strategies that regulate these pathways may be a promising approach for aggregate protein clearancing and consequently the delaying of onset or progression of the disease. However, as the response due to this modulation seems to be time-dependent, finding the right regulation of autophagy may be a potential target for drug development for neurodegenerative diseases. In this way, this review focuses on the role of insulin signaling/resistance and autophagy in some neurodegenerative diseases, discussing pharmacological and non-pharmacological interventions in these diseases.
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http://dx.doi.org/10.3389/fnins.2019.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558407PMC
May 2019

Nrf2/ARE Pathway Modulation by Dietary Energy Regulation in Neurological Disorders.

Front Pharmacol 2019 4;10:33. Epub 2019 Feb 4.

Laboratory of Neuroendocrinopharmacology and Immunomodulation, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of an array of enzymes with important detoxifying and antioxidant functions. Current findings support the role of high levels of oxidative stress in the pathogenesis of neurological disorders. Given the central role played by Nrf2 in counteracting oxidative damage, a number of studies have targeted the modulation of this transcription factor in order to confer neuroprotection. Nrf2 activity is tightly regulated by oxidative stress and energy-based stimuli. Thus, many dietary interventions based on energy intake regulation, such as dietary energy restriction (DER) or high-fat diet (HFD), modulate Nrf2 with consequences for a variety of cellular processes that affect brain health. DER, by either restricting calorie intake or meal frequency, activates Nrf2 thereby triggering its protective effects, whilst HFD inhibit this pathway, thereby exacerbating oxidative stress. Consequently, DER protocols can be valuable strategies in the management of central nervous system (CNS) disorders. Herein, we review current knowledge of the role of Nrf2 signaling in neurological diseases, namely Alzheimer's disease, Parkinson's disease, multiple sclerosis and cerebral ischemia, as well as the potential of energy intake regulation in the management of Nrf2 signaling.
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http://dx.doi.org/10.3389/fphar.2019.00033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369171PMC
February 2019

Klotho deficiency aggravates sepsis-related multiple organ dysfunction.

Am J Physiol Renal Physiol 2019 03 5;316(3):F438-F448. Epub 2018 Dec 5.

Division of Nephrology, University of São Paulo School of Medicine , São Paulo , Brazil.

Sepsis-induced organ failure is characterized by a massive inflammatory response and oxidative stress. Acute kidney injury (AKI) occurs in approximately half of patients in septic shock, and the mortality associated with sepsis-induced AKI is unacceptably high. Klotho is a protein expressed by renal cells and has anti-senescence properties. Klotho has also been shown to protect the kidneys in ischemia-reperfusion injury and to have antioxidant properties. To analyze the role of Klotho in sepsis-related organ dysfunction and AKI, we used a cecal ligation and puncture (CLP) model of sepsis in heterozygous Klotho-haploinsufficient mice and their wild-type littermates (CLP- Kl/+ and CLP-WT mice, respectively). In comparison with the CLP-WT mice, CLP- Kl/+ mice showed lower survival, impaired renal function, impaired hepatic function, greater oxidative stress, upregulation of inflammatory pathways (at the systemic and kidney tissue levels), and increased NF-κB activation. It is noteworthy that CLP- Kl/+ mice also showed lower heart-rate variability, less sympathetic activity, impaired baroreflex sensitivity to sodium nitroprusside, and a blunted blood pressure response to phenylephrine. We also demonstrated that sepsis creates a state of acute Klotho deficiency. Given that low Klotho expression exacerbates sepsis and multiple organ dysfunction, Klotho might play a protective role in sepsis, especially in elderly individuals in whom Klotho expression is naturally reduced.
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http://dx.doi.org/10.1152/ajprenal.00625.2017DOI Listing
March 2019

Repeated Restraint Stress Decreases Na,K-ATPase Activity via Oxidative and Nitrosative Damage in the Frontal Cortex of Rats.

Neuroscience 2018 11 12;393:273-283. Epub 2018 Oct 12.

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo 05508-000, Brazil. Electronic address:

Chronic psychogenic stress can increase neuronal calcium influx and generate the intracellular accumulation of oxidative (ROS) and nitrosative (RNS) reactive species, disrupting synaptic transmission in the brain. These molecules impair the Na,K-ATPase (NKA) activity, whose malfunction has been related to neuropsychiatric disorders, including anxiety, depression, schizophrenia, and neurodegenerative diseases. In this study, we assessed how 14 days of restraint stress in rats affect NKA activity via oxidative/nitrosative damage in the frontal cortex (FCx), a crucial region for emotional and cognitive control. One day after the last stress session (S14 + 1d), but not immediately after the last stress session (S14), α2,3-NKA activity was significantly reduced in the FCx, without changes in the protein levels. The S14 + 1d animals also showed increased lipid peroxidation, iNOS, and AP-1 activities, as well as TNF-α protein levels, evidencing oxidative stress and neuroinflammation. No cellular death or neurodegeneration was observed in the FCx of S14 + 1d animals. Pharmacological inhibition of iNOS or COX-2 before each stress session prevented lipid peroxidation and the α2,3-NKA activity loss. Our results show that repeated restraint exposure for 14 days decreases the activity of α2,3-NKA in FCx 24 h after the last stress, an effect associated with augmented inflammatory response and oxidative and nitrosative damage and suggest new pathophysiological roles to neuroinflammation in neuropsychiatric diseases.
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http://dx.doi.org/10.1016/j.neuroscience.2018.09.037DOI Listing
November 2018

Ouabain attenuates oxidative stress and modulates lipid composition in hippocampus of rats in lipopolysaccharide-induced hypocampal neuroinflammation in rats.

J Cell Biochem 2019 03 27;120(3):4081-4091. Epub 2018 Sep 27.

Laboratory of Cell Biochemistry, Campus Centro-Oeste Dona Lindu, Federal University of São João del Rei, Divinópolis, Brazil.

Our study aimed to analyze the effect of ouabain (OUA) administration on lipopolysaccharide (LPS)-induced changes in hippocampus of rats. Oxidative parameters were analyzed in Wistar rats after intraperitoneal injection of OUA (1.8 µg/kg), LPS (200 µg/kg), or OUA plus LPS or saline. To reach our goal, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), in addition to levels of reduced glutathione (GSH), protein carbonyl (PCO) and lipid peroxidation (LPO) were evaluated. We also analyzed the membrane lipid profile and some important lipids for the nervous system, such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidic acid and sphingomyelin. The group that received only LPS showed increased oxidative stress, as evidenced by an increase in LPO (about twice), PCO (about three times) levels, and CAT activity (80%). Conversely, administration of LPS decreased GSH levels (55%), and GPx activity (30%), besides a reduction in the amount of PI (60%) and PC (45%). By other side, OUA alone increased the amount of PI (45%), PE (85%), and PC (70%). All harmful effects recorded were attenuated by OUA, suggesting a protective effect against LPS-induced oxidative stress. The relevance of our results extends beyond changes in oxidative parameters induced by LPS, because nanomolar doses of OUA may be useful in neurodegenerative models. Other studies on other cardenolides and substances related issues, as well as the development of new molecules derived from OUA, could also be useful in general oxidative and/or cellular stress, a condition favoring the appearance of neuronal pathologies.
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http://dx.doi.org/10.1002/jcb.27693DOI Listing
March 2019

NO-Dependent Akt Inactivation by S-Nitrosylation as a Possible Mechanism of STZ-Induced Neuronal Insulin Resistance.

J Alzheimers Dis 2018 ;65(4):1427-1443

Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.

Sporadic Alzheimer's disease (sAD) is associated with energy metabolism deficiency and impairment of insulin receptor (IR) signaling in the brain. In this context, low doses of intracerebroventricular (icv) injection of streptozotocin (STZ) in rodents has been used as an experimental model of sAD which leads to an insulin-resistant brain state and neurodegeneration. However, the STZ effects on brain insulin signaling-related proteins it is not appropriately elucidated. The aim of this study was to evaluate the beginning and progression of alterations in the brain IR pathway of rats after 1, 3, 5, and 7 days of STZ injection and investigate intracellular signaling involved on STZ induced insulin resistance. We observed that STZ injection causes cognitive impairment in the animals, a temporal variation of the insulin signaling-related proteins and apoptosis cell death in the hippocampus. We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase (PI3K) activity in the Neuro-2a cells through protein kinase B (Akt) inactivation by S-nitrosylation, which could upregulate GSK3-β activity. STZ ability to cause an insulin-resistant neuron state involves NO production and ROS production which may play an important role in the mechanism linked to STZ-induced neurotoxicity. The icv injection of STZ model and STZ exposed Neuro-2a cells may be potential experimental models for assessing molecules related to the pathogenesis of sAD.
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http://dx.doi.org/10.3233/JAD-180284DOI Listing
August 2019

Hyperglycemia induces inflammatory mediators in the human chorionic villous.

Cytokine 2018 11 13;111:41-48. Epub 2018 Aug 13.

Graduate Program in Gynecology, Obstetrics, and Mastology, Botucatu Medical School, São Paulo State University-UNESP, São Paulo, Brazil. Electronic address:

This study was based on the hypothesis that IL-1β and its central regulator, the inflammasome, may play a role in the inflammatory condition exhibited by placental tissues from mothers with different gestational hyperglycemia levels. Pregnant women were classified according to the glycemic reference as non-diabetic (n = 15), mild gestational hyperglycemia (n = 15), gestational diabetes mellitus (n = 15) and type 2 diabetes mellitus (n = 15). We investigated levels of pro-inflammatory factors in maternal plasma and placental tissues (by ELISA or immunohistochemistry) and, NFKB activity (by electrophoretic mobility shift assay) and inflammasome protein expression (by Western blot) in chorionic villous. Maternal plasma and placental levels of inflammatory factors (IL-1β, IL-6, and MCP-1) were increased during all hyperglycemic conditions. Villous stroma cells showed strong immunoreactivity to CD68. In addition, with syncytiotrophoblast, the villous stroma cells were also stained to detect iNOS, MCP-1, TLR2, and TLR4. Although the levels of protein had fluctuated in the groups, NLRP1, NLRP3, ASC, and Caspase 1 were up-regulated in all hyperglycemic groups suggesting the inflammasome may be assembled in these pregnant women. The NFKB activity also exhibited higher levels in hyperglycemic groups, which might imply in pro-inflammatory cytokines production. In summary, increased maternal glucose levels during pregnancy changed systemic and placental inflammatory patterns, which occurred in parallel with the expression of inflammasome factors and processing and secretion of the pro-inflammatory cytokine IL-1β. These results suggest an inflammatory condition in all gestational hyperglycemic conditions, even in hyperglycemia that is less severe than gestational or overt diabetes, likely associated with inflammasome activation and inflammatory cytokine secretion. Inflammasome activation as a possible source of inflammatory factors may be an important target to be considered while managing hyperglycemia and preventing adverse pregnancy outcomes.
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http://dx.doi.org/10.1016/j.cyto.2018.07.020DOI Listing
November 2018

Ouabain increases neuronal branching in hippocampus and improves spatial memory.

Neuropharmacology 2018 09 9;140:260-274. Epub 2018 Aug 9.

Department of Pharmacology, Institute of Biomedical Science I University of São Paulo, Room 338, Av. Prof. Lineu Prestes, 1524, ICB I, Cidade Universitária, 05508-900, São Paulo, SP. Brazil. Electronic address:

Previous research shows Ouabain (OUA) to bind Na, K-ATPase, thereby triggering a number of signaling pathways, including the transcription factors NFᴋB and CREB. These transcription factors play a key role in the regulation of BDNF and WNT-β-catenin signaling cascades, which are involved in neuroprotection and memory regulation. This study investigated the effects of OUA (10 nM) in the modulation of the principal signaling pathways involved in morphological plasticity and memory formation in the hippocampus of adult rats. The results show intrahippocampal injection of OUA 10 nM to activate the Wnt/β-Catenin signaling pathway and to increase CREB/BDNF and NFᴋB levels. These effects contribute to important changes in the cellular microenvironment, resulting in enhanced levels of dendritic branching in hippocampal neurons, in association with an improvement in spatial reference memory and the inhibition of long-term memory extinction.
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http://dx.doi.org/10.1016/j.neuropharm.2018.08.008DOI Listing
September 2018

Editorial: Updates and New Concepts in Regulation of Proinflammatory Gene Expression by Steroid Hormones.

Front Endocrinol (Lausanne) 2018 27;9:191. Epub 2018 Apr 27.

Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.3389/fendo.2018.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934434PMC
April 2018

Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis.

J Cereb Blood Flow Metab 2019 08 1;39(8):1544-1556. Epub 2018 Mar 1.

2 Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.

Mutations of the β-glucuronidase protein α-Klotho have been associated with premature aging, and altered cognitive function. Although highly expressed in specific areas of the brain, Klotho functions in the central nervous system remain unknown. Here, we show that cultured hippocampal neurons respond to insulin and glutamate stimulation by elevating Klotho protein levels. Conversely, AMPA and NMDA antagonism suppress neuronal Klotho expression. We also provide evidence that soluble Klotho enhances astrocytic aerobic glycolysis by hindering pyruvate metabolism through the mitochondria, and stimulating its processing by lactate dehydrogenase. Pharmacological inhibition of FGFR1, Erk phosphorylation, and monocarboxylic acid transporters prevents Klotho-induced lactate release from astrocytes. Taken together, these data suggest Klotho is a potential new player in the metabolic coupling between neurons and astrocytes. Neuronal glutamatergic activity and insulin modulation elicit Klotho release, which in turn stimulates astrocytic lactate formation and release. Lactate can then be used by neurons and other cells types as a metabolic substrate.
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http://dx.doi.org/10.1177/0271678X18762700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681535PMC
August 2019

EPIC Trial: education programme impact on serum phosphorous control in CKD 5D patients on hemodialysis.

J Bras Nefrol 2017 Oct-Dec;39(4):398-405

Universidade de São Paulo, Instituto de Ciências Biomédicas, Departamento de Farmacologia, São Paulo - SP, Brazil.

Introduction: In stage 5D chronic kidney disease (CKD 5D) patients, the encouragement of treatment adherence by health professionals is a significant clinical challenge.

Objectives: This study evaluates the impact of a nutritional education programme on hyperphosphatemia, utilizing the transtheoretical model of behavior change (TMBC).

Subjects And Methods: A prospective interventional study comprising 179 CKD 5D patients with hypophosphatemia. The 4-month educational programme took place during dialysis sessions. Demographic and laboratory data were evaluated, whilst the TMBC was utilized both pre- and post-intervention.

Results: 132 patients showed a positive change and significant reduction in phosphate levels, whilst 47 patients showed a negative change and little reduction in phosphate levels. Positive changes were identified at different levels of literacy. 117/179 participants had ongoing treatment with sevelamer throughout the trial period. 61 patients with intact parathyroid hormone (iPTH) < 300pg/ml showed phosphate level reductions, whilst 118 patients with iPTH > 300 pg/ml also showed a decrease in phosphate levels.

Conclusions: Nutritional education programmes can achieve excellent results when appropriately applied. An education programme may be effective across different literacy levels.
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http://dx.doi.org/10.5935/0101-2800.20170072DOI Listing
September 2018

Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction.

PLoS One 2017 12;12(12):e0189535. Epub 2017 Dec 12.

Department of Physiology & Biophysics, Biomedical Sciences Institute, University of Sao Paulo, Sao Paulo, SP, Brazil.

Exercise training reduces renin-angiotensin system (RAS) activation, decreases plasma and tissue oxidative stress and inflammation in hypertension. However, the temporal nature of these phenomena in response to exercise is unknown. We sought to determine in spontaneously hypertensive rats (SHR) and age-matched WKY controls the weekly effects of training on blood pressure (BP), plasma and left ventricle (LV) Ang II and Ang-(1-7) content (HPLC), LV oxidative stress (DHE staining), gene and protein expression (qPCR and WB) of pro-inflammatory cytokines, antioxidant enzymes and their consequence on hypertension-induced cardiac remodeling. SHR and WKY were submitted to aerobic training (T) or maintained sedentary (S) for 8 weeks; measurements were made at weeks 0, 1, 2, 4 and 8. Hypertension-induced cardiac hypertrophy was accompanied by acute plasma Ang II increase with amplified responses during the late phase of LV hypertrophy. Similar pattern was observed for oxidative stress markers, TNF alpha and interleukin-1β, associated with cardiomyocytes' diameter enlargement and collagen deposition. SHR-T exhibited prompt and marked decrease in LV Ang II content (T1 vs T4 in WKY-T), normalized oxidative stress (T2), augmented antioxidant defense (T4) and reduced both collagen deposition and inflammatory profile (T8), without changing cardiomyocytes' diameter and LV hypertrophy. These changes were accompanied by decreased plasma Ang II content (T2-T4) and reduced BP (T8). SHR-T and WKY-T showed parallel increases in LV and plasma Ang-(1-7) content. Our data indicate that early training-induced downregulation of LV ACE-AngII-AT1 receptor axis is a crucial mechanism to reduce oxidative/pro-inflammatory profile and improve antioxidant defense in SHR-T, showing in addition this effect precedes plasma RAS deactivation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189535PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726656PMC
January 2018

Ouabain attenuates the oxidative stress induced by lipopolysaccharides in the cerebellum of rats.

J Cell Biochem 2018 02 18;119(2):2156-2167. Epub 2017 Oct 18.

Laboratório de Bioquímica Celular, Universidade Federal de São João del Rei, Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil.

Our study aimed to analyze the effect of ouabain administration on lipopolysaccharide (LPS)-induced changes in oxidative parameters, membrane lipid composition, and the activities of some important enzymes of the nervous system. The content of phospholipids, cholesterol, and gangliosides were analyzed in Wistar rats after intraperitoneal injection of ouabain (1.8 μg/kg), LPS (200 μg/kg), or saline. Oxidative parameters were also evaluated, including the activities of superoxide dismutase, catalase and glutathione peroxidase, the levels of glutathione and lipid peroxidation, as well as Na,K-ATPase activity and the level of glutamate transporter EAAT4. Administration of LPS resulted in increased oxidative stress, as evidenced by an increase in lipid peroxidation levels, glutathione peroxidase activity, decreased catalase activity and reduced glutathione levels. All changes recorded were attenuated by pretreatment with ouabain. Administration of ouabain plus LPS enhanced the total ganglioside content and EAAT4 levels, but failed to alter the Na,K-ATPase activity. Our data suggest a neuroprotective effect of ouabain against LPS-induced oxidative stress by promoting membrane lipid remodeling and increasing the expression of glutamate transporter EAAT4. Our results emphasize that the observed oxidative stress is not correlated with Na,K-ATPase, but with a possible ouabain-mediated effect on cellular signaling. The relevance of our results extends beyond LPS-induced changes in oxidative parameters, as nanomolar doses of ouabain might prove useful in neurodegenerative models. Further study of other cardenolides and related molecules, as well as the development of new molecules derived from ouabain, could also prove useful in the fight against the oxidative and/or general cell stress triggered by neuronal pathologies.
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http://dx.doi.org/10.1002/jcb.26377DOI Listing
February 2018

Alpha 2 Na,K-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells.

Sci Rep 2017 07 7;7(1):4894. Epub 2017 Jul 7.

Department of Pharmacology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.

Ouabain (OUA) is a cardiac glycoside that binds to Na,K-ATPase (NKA), a conserved membrane protein that controls cell transmembrane ionic concentrations and requires ATP hydrolysis. At nM concentrations, OUA activates signaling pathways that are not related to its typical inhibitory effect on the NKA pump. Activation of these signaling pathways protects against some types of injury of the kidneys and central nervous system. There are 4 isoforms of the alpha subunit of NKA, which are differentially distributed across tissues and may have different physiological roles. Glial cells are important regulators of injury and inflammation in the brain and express the α1 and α2 NKA isoforms. This study investigated the role of α2 NKA in OUA modulation of the neuroinflammatory response induced by lipopolysaccharide (LPS) in mouse primary glial cell cultures. LPS treatment increased lactate dehydrogenase release, while OUA did not decrease cell viability and blocked LPS-induced NF-κB activation. Silencing α2 NKA prevented ERK and NF-κB activation by LPS. α2 NKA also regulates TNF-α and IL-1β levels. The data reported here indicate a significant role of α2 NKA in regulating central LPS effects, with implications in the associated neuroinflammatory processes.
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http://dx.doi.org/10.1038/s41598-017-05075-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501845PMC
July 2017

NADPH oxidase contributes to streptozotocin-induced neurodegeneration.

Neuroscience 2017 09 4;358:227-237. Epub 2017 Jul 4.

Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory. The neurodegeneration induced by AD has been linked to oxidative damage. However, little is known about the involvement of NADPH oxidase 2 (Nox2), a multisubunit enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, in the pathogenesis of AD. The main purpose of this study was to investigate the involvement of Nox2 in memory, in AD-related brain abnormalities, oxidative damage, inflammation and neuronal death in the hippocampus in the streptozotocin (STZ)-induced AD-like state by comparing the effects of that drug on mice lacking gp91 and wild-type (Wt) mice. Nox2 gene expression was found increased in Wt mice after STZ injection. In object recognition test, Wt mice injected with STZ presented impairment in short- and long-term memory, which was not observed following Nox2 deletion. STZ treatment induced increased phosphorylation of Tau and increased amyloid-β, apoptosis-inducing factor (AIF) and astrocyte and microglial markers expression in Wt mice but not in gp91. STZ treatment increased oxidative damage and pro-inflammatory cytokines' release in Wt mice, which was not observed in gp91 mice. Nox2 deletion had a positive effect on the IL-10 baseline production, suggesting that this cytokine might contribute to the neuroprotection mechanism against STZ-induced neurodegeneration. In summary, our data suggest that the Nox2-dependent reactive oxygen species (ROS) generation contributes to the STZ-induced AD-like state.
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http://dx.doi.org/10.1016/j.neuroscience.2017.06.050DOI Listing
September 2017

Effect of tryptase inhibition on joint inflammation: a pharmacological and lentivirus-mediated gene transfer study.

Arthritis Res Ther 2017 06 6;19(1):124. Epub 2017 Jun 6.

Department of Pharmacology, Universidade Federal de São Paulo - Escola Paulista de Medicina (UNIFESP-EPM), Rua 03 de Maio, São Paulo, 04044-020, Brazil.

Background: Increasing evidences indicate that an unbalance between tryptases and their endogenous inhibitors, leading to an increased proteolytic activity, is implicated in the pathophysiology of rheumatoid arthritis. The aim of the present study was to evaluate the impact of tryptase inhibition on experimental arthritis.

Methods: Analysis of gene expression and regulation in the mouse knee joint was performed by RT-qPCR and in situ hybridization. Arthritis was induced in male C57BL/6 mice with mBSA/IL-1β. Tryptase was inhibited by two approaches: a lentivirus-mediated heterologous expression of the human endogenous tryptase inhibitor, sperm-associated antigen 11B isoform C (hSPAG11B/C), or a chronic treatment with the synthetic tryptase inhibitor APC366. Several inflammatory parameters were evaluated, such as oedema formation, histopathology, production of IL-1β, -6, -17A and CXCL1/KC, myeloperoxidase and tryptase-like activities.

Results: Spag11c was constitutively expressed in chondrocytes and cells from the synovial membrane in mice, but its expression did not change 7 days after the induction of arthritis, while tryptase expression and activity were upregulated. The intra-articular transduction of animals with the lentivirus phSPAG11B/C or the treatment with APC366 inhibited the increase of tryptase-like activity, the late phase of oedema formation, the production of IL-6 and CXCL1/KC. In contrast, neutrophil infiltration, degeneration of hyaline cartilage and erosion of subchondral bone were not affected.

Conclusions: Tryptase inhibition was effective in inhibiting some inflammatory parameters associated to mBSA/IL-1β-induced arthritis, notably late phase oedema formation and IL-6 production, but not neutrophil infiltration and joint degeneration. These results suggest that the therapeutic application of tryptase inhibitors to rheumatoid arthritis would be restrained to palliative care, but not as disease-modifying drugs. Finally, this study highlighted lentivirus-based gene delivery as an instrumental tool to study the relevance of target genes in synovial joint physiology and disease.
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http://dx.doi.org/10.1186/s13075-017-1326-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461776PMC
June 2017

The relevance of α-KLOTHO to the central nervous system: Some key questions.

Ageing Res Rev 2017 Jul 18;36:137-148. Epub 2017 Mar 18.

School of Life, Health & Chemical Sciences, The Open University, Milton Keynes MK7 6AA, United Kingdom. Electronic address:

α-Klotho is well described as an anti-aging protein, with critical roles in kidney function as a transmembrane co-receptor for FGF23, and as a soluble factor in serum. α-Klotho is also expressed in the choroid plexus, where it is released into the cerebrospinal fluid. Nonetheless, α-Klotho is also expressed in the brain parenchyma. Accumulating evidence indicates that this pool of α-Klotho, which we define as brain α-Klotho, may play important roles as a neuroprotective factor and in promoting myelination, thereby supporting healthy brain aging. Here we summarize what is known about brain α-Klotho before focusing on the outstanding scientific questions related to its function. We believe there is a need for in vitro studies designed to distinguish between brain α-Klotho and other pools of α-Klotho, and for a greater understanding of the basic function of soluble α-Klotho. The mechanism by which the human KL-VS variant affects cognition also requires further elucidation. To help address these questions we suggest some experimental approaches that other laboratories might consider. In short, we hope to stimulate fresh ideas and encourage new research approaches that will allow the importance of α-Klotho for the aging brain to become clear.
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http://dx.doi.org/10.1016/j.arr.2017.03.003DOI Listing
July 2017

Exercise training decreases NADPH oxidase activity and restores skeletal muscle mass in heart failure rats.

J Appl Physiol (1985) 2017 Apr 19;122(4):817-827. Epub 2017 Jan 19.

School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil;

We have recently demonstrated that NADPH oxidase hyperactivity, NF-κB activation, and increased p38 phosphorylation lead to atrophy of glycolytic muscle in heart failure (HF). Aerobic exercise training (AET) is an efficient strategy to counteract skeletal muscle atrophy in this syndrome. Therefore, we tested whether AET would regulate muscle redox balance and protein degradation by decreasing NADPH oxidase hyperactivity and reestablishing NF-κB signaling, p38 phosphorylation, and proteasome activity in plantaris muscle of myocardial infarcted-induced HF (MI) rats. Thirty-two male Wistar rats underwent MI or fictitious surgery (SHAM) and were randomly assigned into untrained (UNT) and trained (T; 8 wk of AET on treadmill) groups. AET prevented HF signals and skeletal muscle atrophy in MI-T, which showed an improved exercise tolerance, attenuated cardiac dysfunction and increased plantaris fiber cross-sectional area. To verify the role of inflammation and redox imbalance in triggering protein degradation, circulating TNF-α levels, NADPH oxidase profile, NF-κB signaling, p38 protein levels, and proteasome activity were assessed. MI-T showed a reduced TNF-α levels, NADPH oxidase activity, and Nox2 mRNA expression toward SHAM-UNT levels. The rescue of NADPH oxidase activity induced by AET in MI rats was paralleled by reducing nuclear binding activity of the NF-κB, p38 phosphorylation, atrogin-1, mRNA levels, and 26S chymotrypsin-like proteasome activity. Taken together our data provide evidence for AET improving plantaris redox homeostasis in HF associated with a decreased NADPH oxidase, redox-sensitive proteins activation, and proteasome hyperactivity further preventing atrophy. These data reinforce the role of AET as an efficient therapy for muscle wasting in HF. This study demonstrates, for the first time, the contribution of aerobic exercise training (AET) in decreasing muscle NADPH oxidase activity associated with reduced reactive oxygen species production and systemic inflammation, which diminish NF-κB overactivation, p38 phosphorylation, and ubiquitin proteasome system hyperactivity. These molecular changes counteract plantaris atrophy in trained myocardial infarction-induced heart failure rats. Our data provide new evidence into how AET may regulate protein degradation and thus prevent skeletal muscle atrophy.
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http://dx.doi.org/10.1152/japplphysiol.00182.2016DOI Listing
April 2017

Chronic nicotine treatment decreases LPS signaling through NF-κB and TLR-4 modulation in the hippocampus.

Neurosci Lett 2017 01 29;636:218-224. Epub 2016 Oct 29.

Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

The hippocampus is a brain region that is rich in nicotinic acetylcholine receptors (nAChRs), especially the α7 subtype. The hippocampus is severely affected in disorders that have a neuroinflammatory component, such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Previous studies demonstrated both in vivo and in vitro that nicotine inhibits immunological responses, including those that are triggered by the inflammatory agent lipopolysaccharide (LPS), the endotoxin of Gram-negative bacteria. The present study investigated whether chronically administered nicotine interferes with the nuclear binding of nuclear factor-κB (NF-κB) and the expression of LPS-induced inflammatory response genes. The results indicated that chronic nicotine administration (0.1mg/kg, s.c., 14days) inhibited the LPS-induced nuclear binding of NF-κB and mRNA expression levels of Tnf, Il1b, Nos2, and Tlr4. The presence of both the selective α7 nAChR antagonist methyllycaconitine (MLA; 5.0mg/kg i.p., 14days) and the nonselective nAChR antagonist mecamylamine (Meca; 1.0mg/kg, s.c., 14days) reversed the inhibitory effects of nicotine. These results suggest that the chronic activation of α7- and αβ-containing nAChRs reduces acute inflammatory responses in the brain.
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http://dx.doi.org/10.1016/j.neulet.2016.10.056DOI Listing
January 2017

Environmental enrichment protects against stress-induced anxiety: Role of glucocorticoid receptor, ERK, and CREB signaling in the basolateral amygdala.

Neuropharmacology 2017 02 1;113(Pt A):457-466. Epub 2016 Nov 1.

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, 05508-000, Brazil. Electronic address:

Environmental enrichment (EE) is an experimental animal model that enhances an animal's opportunity to interact with sensory, motor, and social stimuli, compared to standard laboratory conditions. A prominent benefit of EE is the reduction of stress-induced anxiety. The relationship between stress and the onset of anxiety-like behavior has been widely investigated in experimental research, showing a clear correlation with structural changes in the hippocampus and basolateral amygdala (BLA). However, the mechanisms by which EE exerts its protective roles in stress and anxiety remain unclear, and it is not known whether EE reduces the effects of acute stress on animal behavior shortly following the cessation of stress. We found that EE can prevent the emergence of anxiety-like symptoms in rats measured immediately after acute restraint stress (1 h) and this effect is not due to changes in systemic release of corticosterone. Rather, we found that stress promotes a rapid increase in the nuclear translocation of glucocorticoid receptor (GR) in the BLA, an effect prevented by previous EE exposure. Furthermore, we observed a reduction of ERK (a MAPK protein) and CREB activity in the BLA promoted by both EE and acute stress. Finally, we found that EE decreases the expression of the immediate-early gene EGR-1 in the BLA, indicating a possible reduction of neuronal activity in this region. Hyperactivity of BLA neurons has been reported to accompany anxiety-like behavior and changes in this process may be one of the mechanism by which EE exerts its protective effects against stress-induced anxiety.
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http://dx.doi.org/10.1016/j.neuropharm.2016.10.026DOI Listing
February 2017

Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state.

Sci Rep 2016 10 4;6:34581. Epub 2016 Oct 4.

Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto, Brazil.

The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus. In contrast, the genetic deficiency of Nox2 or its pharmacological inhibition with apocynin (APO) results in reductive stress after lipopolysaccharide-(LPS)-cell stimulation, which causes nuclear accumulation of TRX-1 and enhanced transcription of inflammatory mediators through nuclear-factor-(NF)-κB. The NF-κB overactivation is prevented by TRX-1 oxidation using inhibitors of thioredoxin reductase-1 (TrxR-1). The Nox2/TRX-1/NF-κB intracellular signaling pathway is involved in the pathophysiology of chronic granulomatous disease (CGD) and sepsis. In fact, TrxR-1 inhibition prevents nuclear accumulation of TRX-1 and LPS-stimulated hyperproduction of tumor-necrosis-factor-(TNF)-α by monocytes and neutrophils purified from blood of CGD patients, who have deficient Nox2 activity. TrxR-1 inhibitors, either lanthanum chloride (LaCl) or auranofin (AUR), also increase survival rates of mice undergoing cecal-ligation-and-puncture-(CLP). Therefore, our results identify a hitherto unrecognized Nox2-mediated intracellular signaling pathway that contributes to hyperinflammation in CGD and in septic patients. Additionally, we suggest that TrxR-1 inhibitors could be potential drugs to treat patients with sepsis, particularly in those with CGD.
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http://dx.doi.org/10.1038/srep34581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048297PMC
October 2016

The CLOCK trial, a double-blinded randomized controlled trial: Trisodium citrate 30% and minocycline 3 mg/mL plus EDTA 30 mg/mL are effective and safe for catheter patency maintenance among CKD 5D patients on hemodialysis.

Hemodial Int 2017 04 26;21(2):294-304. Epub 2016 Sep 26.

Department of Nephrology, Integrated Centre of Nephrology, Guarulhos, São Paulo State, Brazil.

Introduction: Poor blood flow rate (PF) is highly prevalent among CKD 5D patients with long-term central venous catheters. Heparin catheter lock solutions are commonly used to maintain catheter patency, however the incidence of PF remains high. The purpose of the CLOCK Trial was to evaluate two catheter lock solutions on reduction of PF incidence.

Methods: Seventy-five CKD 5D patients on high-efficiency hemodialysis at the Integrated Centre of Nephrology (Guarulhos, Brazil) were randomized 1:1:1 to receive a lock solution combining minocycline 3 mg/mL with the anticoagulant/chelation agent EDTA 30 mg/mL (M-EDTA) or heparin 1000 IU/mL (H) or trisodium citrate 30% (TSC) vs. Hfor 15 weeks. A total of 68 patients completed the trial in which both investigators and patients were blinded to treatment allocation. The primary end-point was the occurrence of hydraulic resistance and secondary safety end-point was adverse drug reactions related to the lock solutions.

Findings: At the beginning of the trial, 7 patients were excluded from this trial due to their poor catheter care. The incidence of hydraulic resistance was significantly higher among patients on H (18/23) compared to TSC (4/22) and M-EDTA (2/23) lock solutions, (P < 0.001).

Discussion: The CLOCK Trial suggests TSC and M-EDTA may preserve catheter patency better than H. TSC may be a better option due the lack of association with long-term antimicrobial resistance.
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http://dx.doi.org/10.1111/hdi.12492DOI Listing
April 2017

The Influence of Na(+), K(+)-ATPase on Glutamate Signaling in Neurodegenerative Diseases and Senescence.

Front Physiol 2016 2;7:195. Epub 2016 Jun 2.

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo São Paulo, Brazil.

Decreased Na(+), K(+)-ATPase (NKA) activity causes energy deficiency, which is commonly observed in neurodegenerative diseases. The NKA is constituted of three subunits: α, β, and γ, with four distinct isoforms of the catalytic α subunit (α1-4). Genetic mutations in the ATP1A2 gene and ATP1A3 gene, encoding the α2 and α3 subunit isoforms, respectively can cause distinct neurological disorders, concurrent to impaired NKA activity. Within the central nervous system (CNS), the α2 isoform is expressed mostly in glial cells and the α3 isoform is neuron-specific. Mutations in ATP1A2 gene can result in familial hemiplegic migraine (FHM2), while mutations in the ATP1A3 gene can cause Rapid-onset dystonia-Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC), as well as the cerebellar ataxia, areflexia, pescavus, optic atrophy and sensorineural hearing loss (CAPOS) syndrome. Data indicates that the central glutamatergic system is affected by mutations in the α2 isoform, however further investigations are required to establish a connection to mutations in the α3 isoform, especially given the diagnostic confusion and overlap with glutamate transporter disease. The age-related decline in brain α2∕3 activity may arise from changes in the cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG) pathway. Glutamate, through nitric oxide synthase (NOS), cGMP and PKG, stimulates brain α2∕3 activity, with the glutamatergic N-methyl-D-aspartate (NMDA) receptor cascade able to drive an adaptive, neuroprotective response to inflammatory and challenging stimuli, including amyloid-β. Here we review the NKA, both as an ion pump as well as a receptor that interacts with NMDA, including the role of NKA subunits mutations. Failure of the NKA-associated adaptive response mechanisms may render neurons more susceptible to degeneration over the course of aging.
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http://dx.doi.org/10.3389/fphys.2016.00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890531PMC
June 2016

Cardiotonic Steroids as Modulators of Neuroinflammation.

Front Endocrinol (Lausanne) 2016 16;7:10. Epub 2016 Feb 16.

Department of Pharmacology, Institute of Biomedical Science, University of São Paulo , São Paulo , Brazil.

Cardiotonic steroids (CTS) are a class of specific ligands of the Na(+), K(+)- ATPase (NKA). NKA is a P-type ATPase that is ubiquitously expressed and although well known to be responsible for the maintenance of the cell electrochemical gradient through active transport, NKA can also act as a signal transducer in the presence of CTS. Inflammation, in addition to importantly driving organism defense and survival mechanisms, can also modulate NKA activity and memory formation, as well as being relevant to many chronic illnesses, neurodegenerative diseases, and mood disorders. The aim of the current review is to highlight the recent advances as to the role of CTS and NKA in inflammatory process, with a particular focus in the central nervous system.
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http://dx.doi.org/10.3389/fendo.2016.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754428PMC
February 2016

The Role of Steroid Hormones in the Modulation of Neuroinflammation by Dietary Interventions.

Front Endocrinol (Lausanne) 2016 4;7. Epub 2016 Feb 4.

Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Science, University of São Paulo , São Paulo , Brazil.

Steroid hormones, such as sex hormones and glucocorticoids, have been demonstrated to play a role in different cellular processes in the central nervous system, ranging from neurodevelopment to neurodegeneration. Environmental factors, such as calorie intake or fasting frequency, may also impact on such processes, indicating the importance of external factors in the development and preservation of a healthy brain. The hypothalamic-pituitary-adrenal axis and glucocorticoid activity play a role in neurodegenerative processes, including in disorders such as in Alzheimer's and Parkinson's diseases. Sex hormones have also been shown to modulate cognitive functioning. Inflammation is a common feature in neurodegenerative disorders, and sex hormones/glucocorticoids can act to regulate inflammatory processes. Intermittent fasting can protect the brain against cognitive decline that is induced by an inflammatory stimulus. On the other hand, obesity increases susceptibility to inflammation, while metabolic syndromes, such as diabetes, are associated with neurodegeneration. Consequently, given that gonadal and/or adrenal steroids may significantly impact the pathophysiology of neurodegeneration, via their effect on inflammatory processes, this review focuses on how environmental factors, such as calorie intake and intermittent fasting, acting through their modulation of steroid hormones, impact on inflammation that contributes to cognitive and neurodegenerative processes.
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http://dx.doi.org/10.3389/fendo.2016.00009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740355PMC
February 2016

Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus.

Aging (Albany NY) 2015 Dec;7(12):1094-111

Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, Brazil.

Aging is a multifactorial process associated with an increased susceptibility to neurodegenerative disorders which can be related to chronic inflammation. Chronic inflammation, however, can be characterized by the persistent elevated glucocorticoid (GCs) levels, activation of the proinflammatory transcription factor NF-кB, as well as an increase in cytokines. Interestingly, both NF-кB and cytokines can be even modulated by Glycogen Synthase Kinase 3 beta (GSK-3β) activity, which is a key protein that can intermediate inflammation and metabolism, once it has a critical role in AKT signaling pathway, and can also intermediate WNT/β-CATENIN signaling pathway. The aim of this study was to verify age-related changes in inflammatory status, as well as in the AKT and WNT signaling pathways. Results showed an age-related increase in neuroinflammation as indicated by NF-кB activation, TNF-α and GCs increased levels, a decrease in AKT activation and an increase in GSK-3β activity in both 12- and 24- month old animals. Aging also seems to induce a progressive decrease in canonical WNT/β-CATENIN signaling pathway once there is a decrease in DVL-2 levels and in the transcription of Axin2 gene. Little is known about the DVL-2 regulation as well as its roles in WNT signaling pathway, but for the first time it was suggested that DVL-2 expression can be changed along aging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712335PMC
http://dx.doi.org/10.18632/aging.100853DOI Listing
December 2015