Publications by authors named "Carolina Luft"

22 Publications

  • Page 1 of 1

Prenatal stress and KCl-induced depolarization modulate cell death, hypothalamic-pituitary-adrenal axis genes, oxidative and inflammatory response in primary cortical neurons.

Neurochem Int 2021 Jul 5;147:105053. Epub 2021 May 5.

Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. Electronic address:

Maternal stress has been described as an important component in the offspring's cerebral development, altering the susceptibility to diseases in later life. Moreover, the postnatal period is essential for the development and integration of several peripheral and central systems related to the control of homeostasis. Thus, this study aimed to evaluate the effects of prenatal stress on the activation of cortical neurons, by performing experiments both under basal conditions and after KCl-induced depolarization. Female mice were divided in two groups: control and prenatal restraint stress. Cortical neurons from the offspring were obtained at gestational day 18. The effects of prenatal stress and KCl stimulations on cellular mortality, autophagy, gene expression, oxidative stress, and inflammation were evaluated. We found that neurons from PNS mice have decreased necrosis and autophagy after depolarization. Moreover, prenatal stress modulated the HPA axis, as observed by the increased GR and decreased 5HTr1 mRNA expression. The BDNF is an important factor for neuronal function and results demonstrated that KCl-induced depolarization increased the gene expression of BDNF I, BDNF IV, and TRκB. Furthermore, prenatal stress and KCl treatment induced significant alterations in oxidative and inflammatory markers. In conclusion, prenatal stress and stimulation with KCl may influence several markers related to neurodevelopment in cortical neurons from neonate mice, supporting the well-known long-term effects of maternal stress.
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http://dx.doi.org/10.1016/j.neuint.2021.105053DOI Listing
July 2021

Effects of running before pregnancy on long-term memory and hippocampal alterations induced by prenatal stress.

Neurosci Lett 2021 02 19;746:135659. Epub 2021 Jan 19.

Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil; Laboratory of Cellular Biophysics and Inflammation, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. Electronic address:

Studies have shown that an adverse environment in utero influences fetal growth and development, leading to several neuroendocrine and behavioral changes in adult life. Nevertheless, the mechanisms involved in the long-term benefits of pregestational exercise are still poorly understood. Thus, this study aimed to evaluate the effects of physical exercise before the gestational period on memory behavior and gene expression in the hippocampus of adult mice submitted to prenatal stress. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS), and exercise before the gestational period plus PNS (EX + PNS). When adults, male and female offspring were submitted to the object recognition test followed by the hippocampal evaluation of BDNF exons I and IV mRNA expression, as well as hypothalamic-pituitary-adrenal axis related genes. Pregestational exercise did not prevent the decreased recognition index, as well as GR and CRHR1 gene expression observed in PNS males. Conversely, prenatal stress did not influence female memory behavior. Moreover, exercise attenuated the effects of prenatal stress on female BDNF IV gene expression. The results indicate that pregestational exercise was able to prevent the effects of maternal stress on hippocampal BDNF IV gene expression in females, although no effects were seen on the stress-induced memory impairment in males.
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http://dx.doi.org/10.1016/j.neulet.2021.135659DOI Listing
February 2021

Therapeutic effect of uridine phosphorylase 1 (UPP1) inhibitor on liver fibrosis in vitro and in vivo.

Eur J Pharmacol 2021 Jan 22;890:173670. Epub 2020 Oct 22.

Laboratório de Pesquisa Em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, 90619-900, Brazil.

Potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65) is a potent inhibitor of the uridine phosphorylase 1 (UPP1) enzyme. Its non-ionized analog has already demonstrated biological properties by reducing adverse effects caused by the chemotherapeutic 5-fluorouracil (5-FU). In addition, it has been demonstrated that uridine inhibits inflammation and fibrosis in bleomycin lung injury, decreasing collagen production. The purpose of this study was to investigate the in vitro and in vivo effects of CPBMF65 on activated hepatic stellate cells (HSC) and on carbon tetrachloride-induced liver fibrosis in mice. After incubation with CPBMF65, decreased cell proliferation and phenotype reversion were observed in vitro. In addition, CPBMF65 promoted a protective effect on tetrachloride-induced liver fibrosis in mice, demonstrated by its antifibrotic and anti-inflammatory actions. The results of the present study indicate that the UPP1 inhibitor (CPBMF65) may have potential as a novel therapeutic agent for the treatment of liver fibrosis.
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http://dx.doi.org/10.1016/j.ejphar.2020.173670DOI Listing
January 2021

Extracellular DNA in sputum is associated with pulmonary function and hospitalization in patients with cystic fibrosis.

Respir Med 2020 10 2;172:106144. Epub 2020 Sep 2.

Laboratory of Pediatric Physical Activity, Centro Infant, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil. Electronic address:

Background: Elevated extracellular DNA levels are found in the sputum of patients with cystic fibrosis (CF). However, studies investigating the association of extracellular DNA with CF severity are scarce.

Objective: To evaluate the association of extracellular DNA levels with pulmonary function, antibiotic use, and hospitalization in CF patients.

Methods: This cross-sectional study included CF patients aged ≥5 years who were clinically stable and produced spontaneously expectorated sputum. Extracellular DNA in sputum was quantified, and extracellular DNA networks were seen with immunofluorescence microscopy. Also, cell death profile was assessed. Data on pulmonary function, airway colonization, antibiotic use, and hospitalization in the previous year were collected. Patients were divided into two groups based on median DNA level.

Results: Thirty-three patients were included. Their mean age was 16.3 ± 6.2 years, mean forced expiratory volume in the first second (FEV) was 67.0 ± 26.7 (% of the predicted), and mean DNA level was 241.9 ± 147.2 μg/mL. There were significant correlations of DNA level with FEV (r = -0.60; p < 0.001) and forced vital capacity (r = -0.59; p < 0.001). Moreover, patients with higher DNA level (>243.0 μg/mL) had lower FEV (52.1 ± 27.8% vs. 81.1 ± 16.2%; p = 0.001) and required more hospitalizations (68.8% vs. 35.3%; p = 0.05). Additional findings were the presence of extracellular DNA networks and low rates of necrosis and apoptosis.

Conclusion: Elevated extracellular DNA levels in CF sputum are associated with reduced pulmonary function and increased hospitalizations.
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http://dx.doi.org/10.1016/j.rmed.2020.106144DOI Listing
October 2020

Octyl gallate induces hepatic steatosis in HepG2 cells through the regulation of SREBP-1c and PPAR-gamma gene expression.

EXCLI J 2020 6;19:962-971. Epub 2020 Jul 6.

Laboratório de Biofísica Celular e Inflamação, Escola de Ciências da Saúde e da Vida, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil.

Octyl gallate (OG) is an antioxidant commonly used in food, although there is no definition of its acceptable daily intake. There are reports and showing that food additives and drugs can alter lipid metabolism. Lipid droplet accumulation in hepatic cells is one of the main findings in the unregulated lipid metabolism and is strongly related to the development of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of OG on lipid metabolism in the hepatocellular carcinoma cell line (HepG2). The results have shown, for the first time, that treatment with OG increased the overall amount of lipids, the triglyceride concentration, the lipid droplet area, and SREBP-1c and PPAR-γ gene expression. Taken together, the findings indicate that OG induces lipid droplet accumulation in HepG2 cells through the regulation of SREBP-1c and PPAR-γ gene expression without involving mTOR/S6K1 and may contribute to NAFLD when used as a food additive.
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http://dx.doi.org/10.17179/excli2020-2214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415935PMC
July 2020

Maternal separation induces long-term oxidative stress alterations and increases anxiety-like behavior of male Balb/cJ mice.

Exp Brain Res 2020 Sep 12;238(9):2097-2107. Epub 2020 Jul 12.

Developmental Cognitive Neuroscience Lab (DCNL), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Avenida Ipiranga, 6681, prédio 11, sala 936-Partenon, Porto Alegre, RS, 90619-900, Brazil.

Early life stress (ELS) exposure is a well-known risk factor for the development of psychiatric conditions, including anxiety disorder. Preclinical studies show that maternal separation (MS), a classical model of ELS, causes hypothalamic-pituitary-adrenal (HPA) axis alterations, a key contributor to the stress response modulation. Given that HPA axis activation has been shown to induce oxidative stress, it is possible to hypothesize that oxidative stress mediates the relationship between chronic ELS exposure and the development of several disorders. Here, we investigate the effects of MS in the oxidative status [plasma and brain reduced glutathione, catalase and thiobarbituric acid reactive substances (TBARS)], metabolism (glucose, triglycerides and cholesterol) and anxiety-like behaviors in adult Balb/cJ mice. In short, we found that MS increased anxiety-like behaviors in the open field, light/dark test but not in the elevated-plus maze. Animals also presented increased circulating cholesterol, increased TBARS in the plasma and decreased catalase in the hippocampus. Our findings suggest that MS induces long-term alterations in oxidative stress and increased anxiety-like behaviors.
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http://dx.doi.org/10.1007/s00221-020-05859-yDOI Listing
September 2020

Sex-dependent metabolic effects of pregestational exercise on prenatally stressed mice.

J Dev Orig Health Dis 2021 Apr 14;12(2):271-279. Epub 2020 May 14.

Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Stressful events during the prenatal period have been related to hyperactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as metabolic changes in adult life. Moreover, regular exercise may contribute to the improvement of the symptoms associated with stress and stress-related chronic diseases. Therefore, this study aims to investigate the effects of exercise, before the gestation period, on the metabolic changes induced by prenatal stress in adult mice. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS) and exercise before the gestational period plus PNS (EX + PNS). When adults, the plasmatic biochemical analysis, oxidative stress, gene expression of metabolic-related receptors and sex differences were assessed in the offspring. Prenatal stress decreased neonatal and adult body weight when compared to the pregestational exercise group. Moreover, prenatal stress was associated with reduced body weight in adult males. PNS and EX + PNS females showed decreased hepatic catalase. Pregestational exercise prevented the stress-induced cholesterol increase in females but did not prevent the liver mRNA expression reduction on the peroxisome proliferator-activated receptors (PPARs) α and γ in PNS females. Conversely, PNS and EX + PNS males showed an increased PPARα mRNA expression. In conclusion, pregestational exercise prevented some effects of prenatal stress on metabolic markers in a sex-specific manner.
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http://dx.doi.org/10.1017/S2040174420000343DOI Listing
April 2021

CPBMF65, a synthetic human uridine phosphorylase-1 inhibitor, reduces HepG2 cell proliferation through cell cycle arrest and senescence.

Invest New Drugs 2020 12 4;38(6):1653-1663. Epub 2020 May 4.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil.

Hepatocellular carcinoma (HCC) is the most prevalent type of tumor among primary liver tumors and is the second highest cause of cancer-related deaths worldwide. Current therapies are controversial, and more research is needed to identify effective treatments. A new synthetic compound, potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65), is a potent inhibitor of the human uridine phosphorylase-1 (hUP1) enzyme, which controls the cell concentration of uridine (Urd). Urd is a natural pyrimidine nucleoside involved in cellular processes, such as RNA synthesis. In addition, it is considered a promising biochemical modulator, as it may reduce the toxicity caused by chemotherapeutics without impairing its anti-tumor activity. Thus, the objective of this study is to evaluate the effects of CPBMF65 on the proliferation of the human hepatocellular carcinoma cell line (HepG2). Cell proliferation, cytotoxicity, apoptosis, senescence, autophagy, intracellular Urd levels, cell cycle arrest, and drug resistance were analyzed. Results demonstrate that, after incubation with CPBMF65, HepG2 cell proliferation decreased, mainly through cell cycle arrest and senescence, increasing the levels of intracellular Urd and maintaining cell proliferation reduced during chronic treatment. In conclusion, results show, for the first time, the ability of a hUP1 inhibitor (CPBMF65) to reduce HepG2 cell proliferation through cell cycle arrest and senescence.
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http://dx.doi.org/10.1007/s10637-020-00941-2DOI Listing
December 2020

Neostigmine treatment induces neuroprotection against oxidative stress in cerebral cortex of asthmatic mice.

Metab Brain Dis 2020 06 18;35(5):765-774. Epub 2020 Mar 18.

Laboratory of Pediatric Respirology, Infant Center, School of Medical, Pontifical Catholic University of Rio Grande do Sul, PUCRS, Porto Alegre, Brazil.

During chronic inflammatory disease, such asthma, leukocytes can invade the central nervous system (CNS) and together with CNS-resident cells, generate excessive reactive oxygen species (ROS) production as well as disbalance in the antioxidant system, causing oxidative stress, which contributes a large part to neuroinflammation. In this sense, the aim of this study is to investigate the effects of treatment with neostigmine, known for the ability to control lung inflammation, on oxidative stress in the cerebral cortex of asthmatic mice. Female BALB/cJ mice were submitted to asthma model induced by ovalbumin (OVA). Control group received only Dulbecco's phosphate-buffered saline (DPBS). To evaluate neostigmine effects, mice received 80 μg/kg of neostigmine intraperitoneally 30 min after each OVA challenge. Our results revealed for the first time that treatment with neostigmine (an acetylcholinesterase inhibitor that no crosses the BBB) was able to revert ROS production and change anti-oxidant enzyme catalase in the cerebral cortex in asthmatic mice. These results support the communication between the peripheral immune system and the CNS and suggest that acetylcholinesterase inhibitors, such as neostigmine, should be further studied as possible therapeutic strategies for neuroprotection in asthma.
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http://dx.doi.org/10.1007/s11011-020-00558-7DOI Listing
June 2020

Anti-inflammatory effect of octyl gallate in alveolar macrophages cells and mice with acute lung injury.

J Cell Physiol 2020 09 22;235(9):6073-6084. Epub 2020 Jan 22.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Departamento de Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Acute lung injury (ALI) is an inflammatory process, and has high incidence and mortality. ALI and the acute respiratory distress syndrome are two common complications worldwide that result in acute lung failure, sepsis, and death. Pro-inflammatory substances, such as cytokines and chemokines, are responsible for activating the body's defense mechanisms and usually mediate inflammatory processes. Therefore, the research of substances that decrease the uncontrolled response of organism is seen as potential for patients with ALI. Octyl gallate (OG) is a phenolic compound with therapeutic actions namely antimicrobial, antiviral, and antifungal. In this study, we evaluated its action on lipopolysaccharide (LPS)-activated alveolar macrophages RAW 264.7 cells and ALI in male mice. Our results demonstrated protective effects of OG in alveolar macrophages activated with LPS and mice with ALI. The OG treatment significantly decreased the inflammatory markers in both studies in vitro and in vivo. The data suggested that OG can act as an anti-inflammatory agent for ALI.
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http://dx.doi.org/10.1002/jcp.29536DOI Listing
September 2020

Exercise before pregnancy attenuates the effects of prenatal stress in adult mice in a sex-dependent manner.

Int J Dev Neurosci 2020 Apr 5;80(2):86-95. Epub 2020 Feb 5.

Laboratory of Pediatric Physical Activity, Infant Center, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

The present study aimed to investigate the long-term effects of exercise before pregnancy on changes induced by prenatal stress. Female and male Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS), and exercise before the gestational period plus PNS (EX + PNS). As adult, fear/anxiety behavior, corticosterone secretion, expression of hypothalamic-pituitary-adrenal (HPA)-related genes, as well as epigenetic modifications were evaluated. Exercise before gestation did not prevent the increased fear/anxiety behavior in PNS mice. A nearly significant (p = .06) basal corticosterone increase was observed in PNS males and the exercise before pregnancy reduced the stress-induced corticosterone increase in PNS females. In addition, an increase on prefrontal cortex (PFC) CRHR1 gene expression was observed in PNS females, which was attenuated by the exercise before gestation. We have also found a glucocorticoid receptor (GR) gene expression decrease in the prefrontal cortex in PNS males, as well as a histone H3 acetylation decrease (p = .06) close to the significance level. In conclusion, pregestational exercise may attenuate developmental changes induced by prenatal stress in a sex-dependent manner.
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http://dx.doi.org/10.1002/jdn.10001DOI Listing
April 2020

Exenatide induces autophagy and prevents the cell regrowth in HepG2 cells.

EXCLI J 2019 22;18:540-548. Epub 2019 Jul 22.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil.

The incidence of hepatocellular carcinoma (HCC) keeps rising year by year, and became the second leading cause of cancer-related death. Some studies have found that liraglutide, a GLP-1 analog, may decrease the tumor cells proliferation. Due to this, the aim of this work is to investigate the antiproliferative potential of exenatide, another GLP-1 analog. Cell proliferation was assessed by direct count with Trypan blue dye exclusion. Flow cytometry was used to determinate autophagy and nuclear staining. Morphometric analysis was used to verify senescence and apoptosis. The mechanism that induced cell growth inhibition was analyzed by Western Blot. Treatment with exenatide significantly decreases cell proliferation and increases autophagy, both in relation to control and liraglutide. In addition, mTOR inhibition was greater in cells treated with exenatide. In relation to chronic treatment, exenatide does not allow cellular regrowth by preventing some resistance mechanism that the cells can acquire. These results suggest that exenatide has a potent anti-proliferative activity via mTOR modulation and, among the GLP-1 analogs tested, could be in the future an alternative for HCC treatment.
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http://dx.doi.org/10.17179/excli2019-1415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785771PMC
July 2019

Sex differences in the effects of acute stress on cerebral glucose metabolism: A microPET study.

Brain Res 2019 11 26;1722:146355. Epub 2019 Jul 26.

Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS 90619-900, Brazil. Electronic address:

Stress has been considered as a risk factor for the development and aggravation of several diseases. The hypothalamic-pituitary-adrenal axis (HPA) is one of the main actors for the stress response and homeostasis maintenance. Positron emission tomography (PET) has been used to evaluate neuronal activity and to study brain regions that may be related to the HPA axis response. Since neuroimaging is an important tool in detecting neuroendocrine-related changes, we used fluorodeoxyglucose-18 (F-FDG) and positron emission microtomography (microPET) to evaluate sexual differences in the glucose brain metabolism after 10, 30 and 40 min of acute stress in Balb/c mice. We also investigated the effects of restraint stress in blood, liver and adrenal gland F-FDG biodistribution using a gamma counter. A decreased glucose uptake in the whole brain in both females and males was found. Additionally, there were time and sex-dependent alterations in the F-FDG uptake after restraint stress in specific brain regions, indicating that males could be more vulnerable to the short-term effects of acute stress. According to the gamma counter biodistribution, only females showed a significant decreased glucose uptake in the blood, liver and right adrenal after restraint stress. In addition, in comparisons between the sexes, males showed a decreased glucose uptake in the whole brain and in several brain regions compared to females. In conclusion, exposure to acute restraint stress resulted in significant decreased glucose metabolism in the brain, with particular effects in different regions and organs in a sex-specific manner.
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http://dx.doi.org/10.1016/j.brainres.2019.146355DOI Listing
November 2019

Cholinergic anti-inflammatory pathway confers airway protection against oxidative damage and attenuates inflammation in an allergic asthma model.

J Cell Physiol 2020 02 22;235(2):1838-1849. Epub 2019 Jul 22.

Laboratory of Pediatric Respirology, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Hospital Moinhos de Vento, HMV, Porto Alegre, Brazil.

Asthma is characterized by the influx of inflammatory cells, especially of eosinophils as well as reactive oxygen species (ROS) production, driven by the release of the T helper 2 (Th2)-cell-associated cytokines. The cholinergic anti-inflammatory pathway (CAP) inhibit cytokines production and controls inflammation. Thus, we investigated the effects of pharmacological activation of CAP by neostigmine on oxidative stress and airway inflammation in an allergic asthma model. After the OVA challenge, mice were treated with neostigmine. We showed that CAP activation by neostigmine reduced the levels of pro-inflammatory cytokines (IL-4, IL-5, IL-13, IL-1β, and TNF-α), which resulted in a decrease of eosinophils influx. Furthermore, neostigmine also conferred airway protection against oxidative stress, attenuating ROS production through the increase of antioxidant defense, evidenced by the catalase (CAT) activity. We propose, for the first time, that pharmacological activation of the CAP can lead to new possibilities in the therapeutic management of allergic asthma.
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http://dx.doi.org/10.1002/jcp.29101DOI Listing
February 2020

Fructose-1,6-bisphosphate preserves glucose metabolism integrity and reduces reactive oxygen species in the brain during experimental sepsis.

Brain Res 2018 11 19;1698:54-61. Epub 2018 Jun 19.

Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA, Porto Alegre, Brazil; Laboratório de Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul - PUCRS, Porto Alegre, Brazil.

Sepsis is one of the main causes of hospitalization and mortality in Intensive Care Units. One of the first manifestations of sepsis is encephalopathy, reported in up to 70% of patients, being associated with higher mortality and morbidity. The factors that cause sepsis-associated encephalopathy (SAE) are still not well known, and may be multifactorial, as perfusion changes, neuroinflammation, oxidative stress and glycolytic metabolism alterations. Fructose-1,6-bisphosphate (FBP), a metabolite of the glycolytic route, has been reported as neuroprotective agent. The present study used an experimental sepsis model in C57BL/6 mice. We used in vivo brain imaging to evaluate glycolytic metabolism through microPET scans and the radiopharmaceutical F-fluoro-2-deoxy-D-glucose (F-FDG). Brain images were obtained before and 12 h after the induction of sepsis in animals with and without FBP treatment. We also evaluated the treatment effects in the brain oxidative stress by measuring the production of reactive oxygen species (ROS), the activity of catalase (CAT) and glutathione peroxidase (GPx), and the levels of fluorescent marker 2'7'-dichlorofluorescein diacetate (DCF). There was a significant decrease in brain glucose metabolism due to experimental sepsis. A significant protective effect of FBP treatment was observed in the cerebral metabolic outcomes. FBP also modulated the production of ROS, evidenced by reduced CAT activity and lower levels of DCF. Our results suggest that FBP may be a possible candidate in the treatment of SAE.
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http://dx.doi.org/10.1016/j.brainres.2018.06.024DOI Listing
November 2018

Mesenchymal stem cells decrease lung inflammation during sepsis, acting through inhibition of the MAPK pathway.

Stem Cell Res Ther 2017 12 22;8(1):289. Epub 2017 Dec 22.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, CEP 90619-900, Brazil.

Background: Sepsis is a severe medical condition that ranks among the top 10 causes of death worldwide and which has permanently high incidence rates. Mesenchymal stem cells (MSCs) have been found to be potent modulators of immune responses. More importantly, there is evidence that MSCs have a beneficial effect on preclinical models of polymicrobial sepsis. However, the changes caused by the MSCs in the effector cells of the host immune system remain unclear.

Methods: A mouse model of sepsis (male C57BL/6 mice) with three experimental groups was used for experiments in vivo: a control group, an untreated septic group, and a septic group treated with MSCs. In vitro experiments were performed using a cell line of pulmonary macrophages (RAW 264.7) co-cultured with MSCs and stimulated with lipopolysaccharide (LPS).

Results: In vivo we demonstrated that treatment with MSCs was able to reduce the expression of cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB), and thereby decrease the production of inflammatory cytokines. In vitro experiments using a co-culture of macrophages with MSCs showed a decrease in COX-2 and NF-κB, and showed that this reduction was directly related to the ability of MSCs to inhibit phosphorylation of ERK, RSK, and p38, enzymes that belong to the family of mitogen-activated protein kinases (MAPKs).

Conclusions: This study demonstrated that MSCs are able to inhibit the MAPK pathway activation, modulating the inflammatory response during sepsis. This understanding that MSCs can remodel the response of host cells and improve the course of sepsis is essential for developing new treatments for this pathology.
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http://dx.doi.org/10.1186/s13287-017-0734-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741936PMC
December 2017

Mesenchymal stem cells improves survival in LPS-induced acute lung injury acting through inhibition of NETs formation.

J Cell Physiol 2017 12 9;232(12):3552-3564. Epub 2017 Feb 9.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul, Brazil.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of acute hypoxemic respiratory failure resulting from a variety of direct and indirect injuries to the gas exchange parenchyma of the lungs. During the ALI, we have an increase release of proinflammatory cytokines and high reactive oxygen species (ROS) formation. These factors are responsible for the release and activation of neutrophil-derived proteases and the formation of neutrophil extracellular traps (NETs). The excessive increase in the release of NETs cause damage to lung tissue. Recent studies have studies involving the administration of mesenchymal stem cells (MSCs) for the treatment of experimental ALI has shown promising results. In this way, the objective of our study is to evaluate the ability of MSCs, in a lipopolysaccharide (LPS)-induced ALI model, to reduce inflammation, oxidative damage, and consequently decrease the release of NETs. Mice were submitted lung injury induced by intratracheal instillation of LPS and subsequently treated or not with MSCs. Treatment with MSCs was able to modulate pulmonary inflammation, decrease oxidative damage, and reduce the release of NETs. These benefits from treatment are evident when we observe a significant increase in the survival curve in the treated animals. Our results demonstrate that MSCs treatment is effective for the treatment of ALI. For the first time, it is described that MSCs can reduce the formation of NETs and an experimental model of ALI. This finding is directly related to these cells modulate the inflammatory response and oxidative damage in the course of the pathology.
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http://dx.doi.org/10.1002/jcp.25816DOI Listing
December 2017

LPS-induced neonatal stress in mice affects the response profile to an inflammatory stimulus in an age and sex-dependent manner.

Dev Psychobiol 2016 07 8;58(5):600-13. Epub 2016 Mar 8.

Centro Infant, Institute of Biomedical Research (IPB) Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690, 2° andar, Rio Grande do Sul, Porto Alegre, CEP 90610-000, Brazil.

The aim of this study is to evaluate the response to an inflammatory stimulus in mice exposed to LPS-induced neonatal stress at different ages and sexes. Balb/c mice were submitted to intraperitoneal injections on postnatal days 3 and 10 with lipopolysaccharide (nLPS) or saline solution (nSal). At 21 or 60 days, either saline solution was injected or an inflammatory stimulus was induced by the injection of 1% carrageenan. Inflammatory cytokines, reactive oxygen species, and neutrophil extracellular traps (NETs) production were measured in peritoneal fluid. LPS-induced neonatal stress can reduce inflammatory cytokines in males and females. An increase in NETs production was observed when 60 day nLPS animals were compared to 21 day mice in both sexes. The ROS production was not affected by neonatal stress. The results shown here indicate that LPS-induced neonatal stress can alter cytokine production in response to inflammatory stimuli at different ages, in a sex-dependent effect. © 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 600-613, 2016.
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http://dx.doi.org/10.1002/dev.21404DOI Listing
July 2016

Carrageenan-induced inflammation promotes ROS generation and neutrophil extracellular trap formation in a mouse model of peritonitis.

Eur J Immunol 2016 Apr 8;46(4):964-70. Epub 2016 Feb 8.

Centro Infant, Institute of Biomedical Research (IPB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Neutrophil extracellular traps (NETs) are a combination of DNA fibers and granular proteins, such as neutrophil elastase (NE). NETs are released in the extracellular space in response to different stimuli. Carrageenan is a sulfated polysaccharide extracted from Chondrus crispus, a marine algae, used for decades in research for its potential to induce inflammation in different animal models. In this study, we show for the first time that carrageenan injection can induce NET release in a mouse model of acute peritonitis. Carrageenan induced NET release by viable neutrophils with NE and myeloperoxidase (MPO) expressed on DNA fibers. Furthermore, although this polysaccharide was able to stimulate reactive oxygen species (ROS) generation by peritoneal neutrophils, NADPH oxidase derived ROS were dispensable for NET formation by carrageenan. In conclusion, our results show that carrageenan-induced inflammation in the peritoneum of mice can induce NET formation in an ROS-independent manner. These results may add important information to the field of inflammation and potentially lead to novel anti-inflammatory agents targeting the production of NETs.
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http://dx.doi.org/10.1002/eji.201545520DOI Listing
April 2016

Effects of neonatal inflammation on the inflammatory and oxidative profile during experimental sepsis in adult life.

Physiol Behav 2015 Nov 24;151:516-24. Epub 2015 Aug 24.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil; Centro Infant, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil. Electronic address:

The present study aimed to evaluate the long-term effects of neonatal inflammation on the inflammatory and oxidative profile during experimental sepsis in adult life. Neonatal Balb/c mice received different treatments on day 10: LPS i.p. injection (100g/kg) (nLPS) or saline i.p. injection (nSal). As adults, fear/anxiety behavior was evaluated in the elevated plus maze. The following week, saline solution or LPS was administered and, after 12h, serum (inflammatory cytokines), liver (mitochondrial complexes and oxidative stress) and adrenal gland samples (angiotensin II type 1 and 2 receptors) were collected. There was an increase in the fear/anxiety behavior in the nLPS group. Neonatal administration of LPS increased the mRNA expression of the AT1 receptor and decreased the mRNA expression of the AT2 receptor in the adrenal glands of males. The complexes II and II-III increased in the nLPS saline male group when compared to control. The LPS administration in adult females, regardless of the neonatal treatment, induced a decrease of the glutathione enzyme activity. There were no differences in the inflammatory cytokines. The results showed that neonatal inflammation influenced mitochondrial respiratory chain metabolism and angiotensin II receptors in a sex-dependent manner. Balb/c mice fear and anxiety behaviors in adulthood were programmed by early life inflammatory stress.
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http://dx.doi.org/10.1016/j.physbeh.2015.08.023DOI Listing
November 2015

Antioxidant, analgesic and anti-inflammatory effects of lavender essential oil.

An Acad Bras Cienc 2015 Aug 4;87(2 Suppl):1397-408. Epub 2015 Aug 4.

Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, BR.

Several studies have investigated the antinociceptive, immunomodulatory and anti-inflammatory properties of compounds found in the lavender essential oil (LEO), however to date, there is still lack of substantial data. The objective of this study was to assess the antioxidant, anti-inflammatory and antinociceptive effects of lavender essential oil. The 1,1-diphenyl-2-picrylhydrazyl radical decolorization assay was used for antioxidant activity evaluation. The anti-inflammatory activity was tested using two models of acute inflammation: carrageenan-induced pleurisy and croton oil-induced ear edema. The antinociceptive activity was tested using the pain model induced by formalin. LEO has antioxidant activity, which is dose-dependent response. The inflammatory response evoked by carrageenan and by croton oil was reduced through the pre-treatment of animals with LEO. In the pleurisy model, the drug used as positive control, dexamethasone, was more efficacious. However, in the ear swelling, the antiedematogenic effect of the oil was similar to that observed for dexamethasone. In the formalin test, LEO consistently inhibited spontaneous nociception and presented a similar effect to that of tramadol. The results of this study reveal (in vivo) the analgesic and anti-inflammatory activities of LEO and demonstrates its important therapeutic potential.
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http://dx.doi.org/10.1590/0001-3765201520150056DOI Listing
August 2015

Mesenchymal stem cells decrease splenocytes apoptosis in a sepsis experimental model.

Inflamm Res 2014 Sep 3;63(9):719-28. Epub 2014 Jun 3.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga 6681, prédio 12, bloco C, sala 221, Porto Alegre, Rio Grande do Sul, CEP 90619-900, Brazil.

Objective And Design: Mesenchymal stem cells (MSCs) are potent modulators of immune responses. Sepsis is the association of a systemic inflammatory response with an infection. The aim of this study was to test the ability of MSCs derived from adipose tissue, which have immunomodulatory effects, and to inhibit the septic process in an experimental model of mice.

Methods: Three experimental groups (male C57BL/6 mice) were formed for the test: control group, untreated septic group and septic group treated with MSCs (1 × 10(6) cells/animal).

Results: In the control group, there were no deaths; in the untreated septic group, the mortality rate was 100 % within 26 h; in the septic group treated with MSCs, the mortality rate reached 40 % within 26 h. The group treated with MSCs was able to reduce the markers of tissue damage in the liver and pancreas. The treated group had a reduction of inflammatory markers. Furthermore, the MSCs-treated group was able to inhibit the increase of apoptosis in splenocytes observed in the untreated septic group.

Conclusions: Our data showed that MSCs ameliorated the immune response with decrease of inflammatory cytokines and increase anti-inflammatory IL-10; moreover, inhibited splenocytes apoptosis and, consequently, inhibited tissue damage during sepsis.
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http://dx.doi.org/10.1007/s00011-014-0745-1DOI Listing
September 2014