Publications by authors named "Jarbas Rodrigues de Oliveira"

64 Publications

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

Sepsis-Associated Encephalopathy: from Pathophysiology to Progress in Experimental Studies.

Mol Neurobiol 2021 Jun 26;58(6):2770-2779. Epub 2021 Jan 26.

Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA, Porto Alegre, RS, 90050-170, Brazil.

Sepsis is an organ dysfunction caused by an uncontrolled inflammatory response from the host to an infection. Sepsis is the main cause of morbidity and mortality in intensive care units (ICU) worldwide. One of the first organs to suffer from injuries resulting from sepsis is the brain. The central nervous system (CNS) is particularly vulnerable to damage, mediated by inflammatory and oxidative processes, which can cause the sepsis-associated encephalopathy (SAE), being reported in up to 70% of septic patients. This review aims to bring a summary of the main pathophysiological changes and dysfunctions in SAE, and the main focuses of current experimental studies for new treatments and therapies. The pathophysiology of SAE is complex and multifactorial, combining intertwined processes, and is promoted by countless alterations and dysfunctions resulting from sepsis, such as inflammation, neuroinflammation, oxidative stress, reduced brain metabolism, and injuries to the integrity of the blood-brain barrier (BBB). The treatment is limited once its cause is not completely understood. The patient's sedation is far to provide an adequate treatment to this complex condition. Studies and experimental advances are important for a better understanding of its pathophysiology and for the development of new treatments, medicines, and therapies for the treatment of SAE and to reduce its effects during and after sepsis.
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http://dx.doi.org/10.1007/s12035-021-02303-2DOI Listing
June 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

Methoxyeugenol regulates the p53/p21 pathway and suppresses human endometrial cancer cell proliferation.

J Ethnopharmacol 2021 Mar 30;267:113645. Epub 2020 Nov 30.

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

Ethnopharmacological Relevance: Plant-derived compounds are a reservoir of natural chemicals and can act as drug precursors or prototypes and pharmacological probes. Methoxyeugenol is a natural compound found in plant extracts, such as nutmeg (Myristica fragrans), and it presents anthelmintic, antimicrobial, anti-inflammatory activities. Recently, interest in the anticancer activity of plant extracts is increasing and the therapeutic activity of methoxyeugenol against cancer has not yet been explored.

Aim Of The Study: The present study aimed to evaluate the cancer-suppressive role and the molecular signaling pathways of methoxyeugenol in human endometrial cancer (Ishikawa) cell line.

Materials And Methods: Proliferation, viability, and cell toxicity were assessed by direct counting, MTT assay, and LDH enzyme release assay, respectively. Antiproliferative effect were evaluated by nuclear morphological changes along with the cellular mechanisms of apoptosis and senescence by flow cytometry. The underlying molecular and cellular mechanisms were investigated by RT-qPCR, reactive oxygen species (ROS) levels, mitochondrial dysfunction, and proliferative capacity.

Results And Conclusions: Methoxyeugenol treatment significantly inhibited the proliferation and viability of Ishikawa cells. Probably triggered by the higher ROS levels and mitochondrial dysfunction, the gene expression of p53 and p21 increased and the gene expression of CDK4/6 decreased in response to the methoxyeugenol treatment. The rise in nuclear size and acidic vesicular organelles corroborate with the initial senescence-inducing signals in Ishikawa cells treated with methoxyeugenol. The antiproliferative effect was not related to cytotoxicity and proved to effectively reduce the proliferative capacity of endometrial cancer cells even after treatment withdrawal. These results demonstrated that methoxyeugenol has a promising anticancer effect against endometrial cancer by rising ROS levels, triggering mitochondrial instability, and modulating cell signaling pathways leading to an inhibition of cell proliferation.
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http://dx.doi.org/10.1016/j.jep.2020.113645DOI Listing
March 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

Fructose-1,6-bisphosphate induces generation of reactive oxygen species and activation of p53-dependent cell death in human endometrial cancer cells.

J Appl Toxicol 2021 Jul 20;41(7):1050-1062. Epub 2020 Oct 20.

Laboratory of Cellular Biophysics and Inflammation, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.

Fructose-1,6-bisphosphate (F1,6BP), an intermediate of the glycolytic pathway, has been found to play a promising anticancer effect; nevertheless, the mechanisms involved remain poorly understood. The present study aimed to evaluate the effect and mechanisms of F1,6BP in a human endometrial cancer cell line (Ishikawa). F1,6BP showed an antiproliferative and non-cytotoxic effect on endometrial cancer cells. These effects are related to the increase in reactive oxygen species (ROS) levels and mitochondrial membrane potential (ΔΨm). These harmful stimuli trigger the upregulation of the expression of pro-apoptotic genes (p53 and Bax), leading to the reduction of cell proliferation through inducing programmed cell death by apoptosis. Furthermore, F1,6BP-treated cells had the formation of autophagosomes induced, as well as a decrease in their proliferative capacity after withdrawing the treatment. Our results demonstrate that F1,6BP acts as an anticancer agent through the generation of mitochondrial instability, loss of cell function, and p53-dependent cell death. Thus, F1,6BP proves to be a potential molecule for use in the treatment against endometrial cancer.
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http://dx.doi.org/10.1002/jat.4091DOI Listing
July 2021

Resveratrol increases the activation markers and changes the release of inflammatory cytokines of hepatic stellate cells.

Mol Cell Biochem 2021 Feb 19;476(2):649-661. Epub 2020 Oct 19.

Departmento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP, 90035-003, Brazil.

The phytoalexin Resveratrol (3,5,4'-trihydroxystilbene; RSV) has been related to numerous beneficial effects on health by its cytoprotection and chemoprevention activities. Liver fibrosis is characterized by the extracellular matrix accumulation after hepatic injury and can lead to cirrhosis. Hepatic stellate cells (HSC) play a crucial role during fibrogenesis and liver wound healing by changing their quiescent phenotype to an activated phenotype for protecting healthy areas from damaged areas. Strategies on promoting the activated HSC death, the quiescence return or the cellular activation stimuli decrease play an important role on reducing liver fibrosis. Here, we evaluated the RSV effects on some markers of activation in GRX, an HSC model. We further evaluated the RSV influence in the ability of GRX on releasing inflammatory mediators. RSV at 1 and 10 µM did not alter the protein content of α-SMA, collagen I and GFAP; but 50 µM increased the content of these activation-related proteins. Also, RSV did not change the myofibroblast-like morphology of GRX. Interestingly, RSV at 10 and 50 µM decreased the GRX migration and collagen-I gel contraction. Finally, we showed that RSV triggered the increase in the TNF-α and IL-10 content in culture media of GRX while the opposite occurred for the IL-6 content. Altogether, these results suggested that RSV did not decrease the activation state of GRX and oppositely, triggered a pro-activation effect at the 50 µM concentration. However, despite the increase of TNF- α in culture media, these results on IL-6 and IL-10 secretion were in accordance with the anti-inflammatory role of RSV in our model.
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http://dx.doi.org/10.1007/s11010-020-03933-1DOI Listing
February 2021

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

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

Fructose-1,6-bisphosphate prevents pulmonary fibrosis by regulating extracellular matrix deposition and inducing phenotype reversal of lung myofibroblasts.

PLoS One 2019 11;14(9):e0222202. Epub 2019 Sep 11.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America.

Pulmonary fibrosis (PF) is the result of chronic injury where fibroblasts become activated and secrete large amounts of extracellular matrix (ECM), leading to impaired fibroblasts degradation followed by stiffness and loss of lung function. Fructose-1,6-bisphosphate (FBP), an intermediate of glycolytic pathway, decreases PF development, but the underlying mechanism is unknown. To address this issue, PF was induced in vivo using a mouse model, and pulmonary fibroblasts were isolated from healthy and fibrotic animals. In PF model mice, lung function was improved by FBP as revealed by reduced collagen deposition and downregulation of ECM gene expression such as collagens and fibronectin. Fibrotic lung fibroblasts (FLF) treated with FBP for 3 days in vitro showed decreased proliferation, contraction, and migration, which are characteristic of myofibroblast to fibroblast phenotype reversal. ECM-related genes and proteins such as collagens, fibronectin and α-smooth muscle actin, were also downregulated in FBP-treated FLF. Moreover, matrix metalloproteinase (MMP) 1, responsible for ECM degradation, was produced only in fibroblasts obtained from healthy lungs (HLF) and FBP did not alter its expression. On the other hand, tissue inhibitor of metalloproteinase (TIMP)-1, a MMP1 inhibitor, and MMP2, related to fibroblast tissue-invasion, were predominantly produced by FLF and FBP was able to downregulate its expression. These results demonstrate that FBP may prevent bleomycin-induced PF development through reduced expression of collagen and other ECM components mediated by a reduced TIMP-1 and MMP2 expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222202PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738633PMC
April 2020

Association of IL-10 to coronary disease severity in patients with metabolic syndrome.

Clin Chim Acta 2019 Aug 7;495:394-398. Epub 2019 May 7.

Medical School, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 Porto Alegre, RS, Brazil.

Background: Metabolic syndrome (MetS) is a group of risk factors that increase the risk for heart disease. Little is known about the role of IL-10 in the severity of coronary artery disease (CAD) in patients with MetS. We investigated plasma levels of IL-10 and other pro-inflammatory cytokines in patients with MetS with or without severe CAD.

Methods: Cross-sectional study with healthy and MetS individuals. IL-10 and other pro-inflammatory interleukins were analyzed in 90 subjects divided into 3 groups: group 1 (n = 30), patients with MetS without severe CAD; group 2 (n = 30), patients with MetS and severe CAD (history of myocardial infarction or revascularization performed through surgery or percutaneous transluminal coronary angioplasty with or without stent placement); and group 3 (n = 30), healthy individuals.

Results: Levels of IL-12 (p = .018), TNF-α (p = .007) and IL-6 (p = .010) were significantly higher in group 1 when compared to group 3 (p = .003; p = .002; p = .001, respectively). In addition, group 1 presented significantly higher levels of IL-12 (p = .019), TNF-α (p = .026) and IL-6 (p = .020) when compared to group 2. IL-10 levels were significantly higher in group 1 (p = .003) when compared to group 2 (p = .014) and group 3 (p < .001). Only the level of IL-10 was significant to explain the presence of severe CAD, as a protective factor (OR: 0.896; 95%CI: 0.818-0.981) in the logistic regression model.

Conclusions: Higher IL-10 levels in patients with MetS are associated with lower incidence of severe CAD, suggesting a protective effect through its anti-inflammatory activity even in the presence of higher levels of pro-inflammatory cytokines.
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http://dx.doi.org/10.1016/j.cca.2019.05.006DOI Listing
August 2019

Therapeutic effect of DC. extracts on activated hepatic stellate cells.

EXCLI J 2019 18;18:91-105. Epub 2019 Feb 18.

PUCRS, Escola de Ciências, Laboratório de Pesquisa em Biofísica Celular e Inflamação, Porto Alegre, Brazil.

The therapeutic potential of DC. extracts was evaluated through its cytotoxic and antiproliferative effect and their phenotypic reversion property in activated hepatic stellate cells (HSCs). is distributed in Brazil (southeastern and south regions) and used for diuretic effect in folk medicine. Four fractions were obtained from the fractionation of the methanolic extract. Fractions III and IV decreased cell proliferation without increasing cell necrosis markers levels and induced cell cycle arrest in G1 phase. Fraction III induced phenotypic reversion through PPAR-γ activation pathway, while fraction IV did not alter PPAR-α/γ expression levels, suggesting that there is an independent PPAR-α/γ pathway involved. Hydroxybenzoic, chlorogenic and coumaric acids were identified. Fractions III and IV showed antiproliferative effect and ability to induce reversion of activated phenotype of HSCs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449670PMC
February 2019

Metabolic dysfunction in a rat model of early-life scarcity-adversity: Modulatory role of cafeteria diet.

Exp Physiol 2018 11 8;103(11):1481-1493. Epub 2018 Oct 8.

Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.

New Findings: What is the central question of this study? Early-life adversity is associated with increased risk for obesity and metabolic dysfunction. However, it is unclear whether obesity and metabolic dysfunction result from coping strategies to deal with adversity-related emotional dysregulation, a direct programming of systems regulating metabolic function, or a combination of both. What is the main finding and its importance? Early-life adversity increases vulnerability to later-life obesity and metabolic dysfunction, indicating that genetics and adult lifestyle are not the only determinants of obesity and related metabolic dysfunction. Moreover, consumption of cafeteria diet exacerbated metabolic dysfunction associated with early-life adversity, suggesting that poor dietary choices might have a bigger impact in the context of early-life adversity.

Abstract: Early-life adversity has become recognized as an important factor contributing to adult obesity and associated metabolic dysfunction. However, it is unclear whether obesity and metabolic dysfunction associated with early-life adversity result from coping strategies to deal with adversity-related emotional dysregulation, a direct programming of systems regulating metabolic function, or a combination. Interestingly, both early-life adversity and later-life dietary choices affect immune function, favouring pro-inflammatory mechanisms that are associated with obesity-related metabolic dysfunction. To investigate the unique and/or interactive effects of early-life adversity and later-life dietary choices for increased vulnerability to obesity and metabolic dysfunction, and specifically the role of the immune system in this vulnerability, we combined a naturalistic rat model of early-life scarcity-adversity with a rat model of obesity, the cafeteria diet. Our results indicate that early-life adversity alone induces insulin resistance, reduces pancreatic insulin secretion, plasma concentrations of triglycerides and cholesterol, and increases fasting glucose and tumour necrosis factor-α plasma concentrations. Importantly, animals exposed to adverse rearing were more vulnerable to metabolic dysregulation associated with the cafeteria diet, given that they consumed more energy, showed more severe hepatic steatosis and increased concentrations of the pro-inflammatory cytokine interleukin-1β than normally reared animals fed the cafeteria diet. Together, our results suggest that early-life adversity negatively programmes physiological systems that regulate metabolic function and increases vulnerability to obesity and metabolic dysfunction in adulthood. These results highlight the intrinsic relationship between the quality of the early postnatal environment and later-life dietary choices on adult health outcomes.
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http://dx.doi.org/10.1113/EP087171DOI Listing
November 2018

Simvastatin Prevents Progression of Acute on Chronic Liver Failure in Rats With Cirrhosis and Portal Hypertension.

Gastroenterology 2018 11 25;155(5):1564-1577. Epub 2018 Jul 25.

Barcelona Hepatic Hemodynamic Lab, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic de Barcelona, CIBEREHD, Barcelona, Spain; Hepatology, Department of Biomedical Research, Inselspital, University of Bern, Switzerland. Electronic address:

Background & Aims: Cirrhosis and its clinical consequences can be aggravated by bacterial infections, ultimately leading to the development of acute on chronic liver failure (ACLF), characterized by acute decompensation, organ failure, and high mortality within 28 days. Little is known about cellular and molecular mechanisms of ACLF in patients with cirrhosis, so no therapeutic options are available. We developed a sepsis-associated preclinical model of ACLF to facilitate studies of pathogenesis and evaluate the protective effects of simvastatin.

Methods: Male Wistar rats inhaled CCl until they developed cirrhosis (at 10 weeks) or cirrhosis with ascites (at 15-16 weeks). Male Sprague-Dawley rats received bile-duct ligation for 28 days or intraperitoneal thioacetamide for 10 weeks to induce cirrhosis. After induction of cirrhosis, some rats received a single injection of lipopolysaccharide (LPS) to induce ACLF; some were given simvastatin or vehicle (control) 4 hours or 24 hours before induction of ACLF. We collected data on changes in hepatic and systemic hemodynamics, hepatic microvascular phenotype and function, and survival times. Liver tissues and plasma were collected and analyzed by immunoblots, quantitative polymerase chain reaction, immuno(fluoro)histochemistry and immunoassays.

Results: Administration of LPS aggravated portal hypertension in rats with cirrhosis by increasing the severity of intrahepatic microvascular dysfunction, exacerbating hepatic inflammation, increasing oxidative stress, and recruiting hepatic stellate cells and neutrophils. Rats with cirrhosis given LPS had significantly shorter survival times than rats with cirrhosis given the control. Simvastatin prevented most of ACLF-derived complications and increased survival times. Simvastatin appeared to increase hepatic sinusoidal function and reduce portal hypertension and markers of inflammation and oxidation. The drug significantly reduced levels of transaminases, total bilirubin, and ammonia, as well as LPS-mediated activation of hepatic stellate cells in liver tissues of rats with cirrhosis.

Conclusions: In studies of rats with cirrhosis, we found administration of LPS to promote development of ACLF, aggravating the complications of chronic liver disease and decreasing survival times. Simvastatin reduced LPS-induced inflammation and liver damage in rats with ACLF, supporting its use in treatment of patients with advanced chronic liver disease.
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http://dx.doi.org/10.1053/j.gastro.2018.07.022DOI Listing
November 2018

Fructose-1,6-Bisphosphate Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice and Inhibits the Proliferation of Lung Fibroblasts.

Inflammation 2018 Oct;41(5):1987-2001

Laboratório de Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul-PUCRS, Porto Alegre, Brazil.

Pulmonary fibrosis is a specific form of interstitial pneumonia. In addition to the idiopathic cause, it may be caused by drugs such as bleomycin (BLM)-used in the treatment of tumors. Fructose-1,6-bisphosphate (FBP) is a high-energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory, and immunomodulatory effects. The aim of this study was to investigate the effects of FBP on both BLM-induced pulmonary fibrosis in mice and in a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 mice were divided into four groups: control, FBP, BLM, and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally, and survival, body weight, Ashcroft score, and histological analysis were evaluated. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg-intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased the survival rate and reduced body weight loss (BLM vs. BLM plus FBP-p < 0.05). FBP also prevented BLM-induced loss of pulmonary function and decreased BALF inflammatory cells, level of fibrosis, and superficial collagen density (p < 0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer.
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http://dx.doi.org/10.1007/s10753-018-0842-3DOI Listing
October 2018

Octyl gallate reduces ATP levels and Ki67 expression leading HepG2 cells to cell cycle arrest and mitochondria-mediated apoptosis.

Toxicol In Vitro 2018 Apr 26;48:11-25. Epub 2017 Dec 26.

Laboratório de Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul, Av. Ipiranga, 6681, prédio 12, bloco c, Partenon, Porto Alegre, Rio Grande do Sul 90619-900, Brazil.

Octyl gallate (OG) is an antioxidant that has shown anti-tumor, anti-diabetic and anti-amyloidogenic activities. Mitochondria play an important role in hepatocellular carcinoma, mainly by maintaining accelerated cellular proliferation through the production of ATP. Thus, the mitochondria may be a target for antitumor therapies. Here, we investigated the effects of OG in the hepatocarcinoma cell line (HepG2) and the mechanisms involved. We report, for the first time, that treatment with OG for 24h inhibited HepG2 cell growth by decreasing mitochondrial activity and mass, which led to the reduction of ATP levels. This reduction in the energy supply triggered a decrease in Ki67 protein expression, leading cells to cycle arrest. In addition, treatment with two doses of OG for 48h induced loss of mitochondrial functionality, mitochondrial swelling and apoptosis. Finally, we report that HepG2 cells had no resistance to treatment after multiple doses. Collectively, our findings indicate that metabolic dysregulation and Ki67 protein reduction are key events in the initial anti-proliferative action of OG, whereas mitochondrial swelling and apoptosis induction are involved in the action mechanism of OG after prolonged exposure. This suggests that OG targets mitochondria, thus representing a candidate for further research on therapies for hepatocarcinoma.
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http://dx.doi.org/10.1016/j.tiv.2017.12.017DOI Listing
April 2018

Leucine reduces the proliferation of MC3T3-E1 cells through DNA damage and cell senescence.

Toxicol In Vitro 2018 Apr 24;48:1-10. Epub 2017 Dec 24.

Pontifical Catholic University of Rio Grande do Sul - PUCRS, Brazil. Electronic address:

Leucine (Leu) is an essential branched-chain amino acid, present in dairy products, which has been investigated for its important role in cell signaling. The effects of Leu on several kinds of cells have been studied, altough little is known on its action upon bone cells and cell proliferation. Thus, the aim of this study is to investigate the effects of Leu supplementation on the proliferation of pre-osteoblasts from MC3T3-E1 lineage. MC3T3-E1 cells were kept in Alpha medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimitotic. Cells were treated during 48h by adding 50μM of Leu, which corresponds to a 12.5% increase of the amino acid in the culture medium. The evaluation of viability and proliferation of cultured cells was performed using Trypan Blue dye. In order to identify the mechanisms related to the decreased cellular proliferation, assays were performed to assess cytotoxicity, apotosis, oxidative stress, inflammation, autophagy, senescence and DNA damage. Results showed that Leu supplementation decreased cell proliferation by 40% through mechanisms not related to cell necrosis, apoptosis, oxidative stress, autophagy or inhibition of the mTORC1 pathway. On the other hand, Leu supplementation caused DNA damage. In conclusion, Leu caused a negative impact on bone cell proliferation by inducing cell senescence through DNA damage.
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http://dx.doi.org/10.1016/j.tiv.2017.12.015DOI Listing
April 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

Low-intensity pulsed ultrasound (LIPUS) stimulates mineralization of MC3T3-E1 cells through calcium and phosphate uptake.

Ultrasonics 2018 Mar 22;84:290-295. Epub 2017 Nov 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. Electronic address:

The present study aimed to evaluate the effect of low-intensity pulsed ultrasound (LIPUS) on pre-osteoblast mineralization using in vitro bioassays. Pre-osteoblastic MC3T3-E1 cells were exposed to LIPUS at 1 MHz frequency, 0.2 W/cm intensity and 20% duty cycle for 30 min. The analyses were carried out up to 336 h (14 days) after exposure. The concentration of collagen, phosphate, alkaline phosphatase, calcium and transforming growth factor beta 1 (TGF-β1) in cell supernatant and the presence of calcium deposits in the cells were analyzed. Our results showed that LIPUS promotes mineralized nodules formation. Collagen, phosphate, and calcium levels were decreased in cell supernatant at 192 h after LIPUS exposure. However, alkaline phosphatase and TGF-β1 concentrations remained unchanged. Therapeutic pulsed ultrasound is capable of stimulating differentiation and mineralization of pre-osteoblastic MC3T3-E1 cells by calcium and phosphate uptake with consequent hydroxyapatite formation.
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http://dx.doi.org/10.1016/j.ultras.2017.11.011DOI Listing
March 2018

Erratum to: Fructose-1,6-bisphosphate reverts iron-induced phenotype of hepatic stellate cells by chelating ferrous ions.

Biometals 2017 10;30(5):821

Cellular Biophysics and Inflammation Laboratory, 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.

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http://dx.doi.org/10.1007/s10534-017-0043-9DOI Listing
October 2017

Fructose-1,6-bisphosphate reverts iron-induced phenotype of hepatic stellate cells by chelating ferrous ions.

Biometals 2017 08 21;30(4):549-558. Epub 2017 Jun 21.

Cellular Biophysics and Inflammation Laboratory, 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.

Hepatic fibrosis is an extracellular matrix deposition by hepatic stellate cells (HSC). Fibrosis can be caused by iron, which will lead to hydroxyl radical production and cell damage. Fructose-1,6-bisphosphate (FBP) has been shown to deliver therapeutic effects in many pathological situations. In this work, we aimed to test the effects of FBP in HSC cell line, GRX, exposed to an excess of iron (Fe). The Fe-treatment increased cell proliferation and FBP reversed this effect, which was not due to increased necrosis, apoptosis or changes in cell cycle. Oil Red-O staining showed that FBP successfully increased lipid content and lead GRX cells to present characteristics of quiescent HSC. Fe-treatment decreased PPAR-γ expression and increased Col-1 expression. Both effects were reversed by FBP which also decreased TGF-β1 levels in comparison to both control and Fe groups. FBP, also, did not present scavenger activity in the DPPH assay. The treatment with FBP resulted in decreased proliferation rate, Col-1 expression and TGF-β1 release by HSC cells. Furthermore, activated PPAR-γ and increased lipid droplets induce cells to become quiescent, which is a key event to reversion of hepatic fibrosis. FBP also chelates iron showing potential to improve Cell redox state.
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http://dx.doi.org/10.1007/s10534-017-0025-yDOI Listing
August 2017

Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies.

Sci Rep 2017 06 12;7(1):3255. Epub 2017 Jun 12.

Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Lab, IDIBAPS Biomedical Research Institute - CIBEREHD, Barcelona, Spain.

Hepatic stellate cells (HSC) play a key role in the development of chronic liver disease (CLD). Liraglutide, well-established in type 2 diabetes, showed anti-inflammatory and anti-oxidant properties. We evaluated the effects of liraglutide on HSC phenotype and hepatic microvascular function using diverse pre-clinical models of CLD. Human and rat HSC were in vitro treated with liraglutide, or vehicle, and their phenotype, viability and proliferation were evaluated. In addition, liraglutide or vehicle was administered to rats with CLD. Liver microvascular function, fibrosis, HSC phenotype and sinusoidal endothelial phenotype were determined. Additionally, the effects of liraglutide on HSC phenotype were analysed in human precision-cut liver slices. Liraglutide markedly improved HSC phenotype and diminished cell proliferation. Cirrhotic rats receiving liraglutide exhibited significantly improved liver microvascular function, as evidenced by lower portal pressure, improved intrahepatic vascular resistance, and marked ameliorations in fibrosis, HSC phenotype and endothelial function. The anti-fibrotic effects of liraglutide were confirmed in human liver tissue and, although requiring further investigation, its underlying molecular mechanisms suggested a GLP1-R-independent and NF-κB-Sox9-dependent one. This study demonstrates for the first time that liraglutide improves the liver sinusoidal milieu in pre-clinical models of cirrhosis, encouraging its clinical evaluation in the treatment of chronic liver disease.
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http://dx.doi.org/10.1038/s41598-017-02866-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468330PMC
June 2017

Liraglutide, a glucagon-like peptide-1 analog, induce autophagy and senescence in HepG2 cells.

Eur J Pharmacol 2017 Aug 10;809:32-41. Epub 2017 May 10.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil; Laboratório de Imunologia Clínica e Experimental, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil.

It has been reported that glucagon-like peptide-1 (GLP-1) agents have been associated with both the increased risk of cancer and inhibition of tumor growth and metastases. The aim of this study is to evaluate the effect of liraglutide on hepatocellular carcinoma cells - HepG2. Cytometry was used to evaluate mechanism related to decreased cell proliferation. Nuclear staining and morphometric analysis were also used to verify the process that was taking place after treatment with liraglutide, and in order to better understand the mechanism, TGF-β1 was performed. HepG2 cells decreased proliferation after liraglutide treatment without altering oxidative stress levels. Liraglutide was able to induce autophagy and senescence through the increase of TGF-β1 which possibly explains the growth decrease. We have demonstrated that liraglutide has an antiproliferative effect in HepG2 cells inducing autophagy and senescence by the increase of TGF-β1.
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http://dx.doi.org/10.1016/j.ejphar.2017.05.015DOI Listing
August 2017

Mesenchymal stem cells cannot affect mRNA expression of toll-like receptors in different tissues during sepsis.

Inflamm Res 2017 Jul 8;66(7):547-551. Epub 2017 Apr 8.

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.

Objective And Design: Experimental animal models and human clinical studies support a crucial role for TLRs in infectious diseases. The aim of this study was to test the ability of MSCs, which have immunomodulatory effects, of altering the mRNA expression of toll-like receptors during a experimental model of sepsis in different tissues.

Materials And 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 cells/animal). Lungs, cortex, kidney, liver and colon tissue were dissected after 12 h of sepsis induction and TLR2/3/4/9 mRNA were evaluated by RT-qPCR.

Results: We observed a decrease of TLR2 and 9 mRNA expression in the liver of the sepsis group, while TLR3 was decreased in the lung and liver. No change was found between the sepsis group and the sepsis + MSC group.

Conclusions: In this model of experimental sepsis the MSCs were unable to modify the mRNA expression of the different toll-like receptors evaluated.
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http://dx.doi.org/10.1007/s00011-017-1042-6DOI Listing
July 2017

Fructose-1,6-bisphosphate decreases IL-8 levels and increases the activity of pro-apoptotic proteins in HepG2 cells.

Biomed Pharmacother 2017 05 27;89:358-365. Epub 2017 Feb 27.

Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil; Laboratório de Imunologia Clínica e Experimental, Instituto de Pesquisas Biomédicas, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil; Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Brazil.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver tumor that affects the world population. Liver cancer inevitably causes great harms and its treatment is extremely difficult. Its development is related to the existence of chronic liver injury, such as in cirrhosis. Cancer is a disease related to the process of inflammation so, research with anti-inflammatory agents has been performed for the development of anti-tumor drugs. Fructose-1,6-bisphosphate (FBP), a metabolite of the glycolytic route, has shown anti-inflammatory actions. The purpose of this study is to investigate the effect of FBP on HepG2 cells growth and inflammatory parameters. Results showed that FBP decreased the proliferation of HepG2 cells through trypan blue assay, without causing necrosis, shown by the intracellular release of LDH. By flow cytometry, we observed a significant IL-8 decrease which is closely related to the tumoral progression and chemotherapeutic resistance, especially in HCC. Then, we found, by RT-PCR, a high expression level of pro-apoptotic protein, such as Bax and p53, and decreased the expression levels of anti-apoptotic proteins, like Bcl-2 suggesting apoptosis. Finally, our results showed that FBP can be a potential therapeutic agent to slow the progress of HCC.
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http://dx.doi.org/10.1016/j.biopha.2017.01.178DOI Listing
May 2017