Publications by authors named "Ana Angélica Fernandes"

64 Publications

Açai supplementation (Euterpe oleracea Mart.) attenuates cardiac remodeling after myocardial infarction in rats through different mechanistic pathways.

PLoS One 2022 4;17(3):e0264854. Epub 2022 Mar 4.

Internal Medicine Department, Botucatu Medical School, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil.

Myocardial infarction has a high mortality rate worldwide. Therefore, clinical intervention in cardiac remodeling after myocardial infarction is essential. Açai pulp is a natural product and has been considered a functional food because of its antioxidant/anti-inflammatory properties. The aim of the present study was to analyze the effect of açai pulp supplementation on cardiac remodeling after myocardial infarction in rats. After 7 days of surgery, male Wistar rats were assigned to six groups: sham animals fed standard chow (SA0, n = 14), fed standard chow with 2% açai pulp (SA2, n = 12) and fed standard chow with 5% açai pulp (SA5, n = 14), infarcted animals fed standard chow (IA0, n = 12), fed standard chow with 2% açai pulp (IA2, n = 12), and fed standard chow with 5% açai pulp (IA5, n = 12). After 3 months of supplementation, echocardiography and euthanasia were performed. Açai pulp supplementation, after myocardial infarction, improved energy metabolism, attenuated oxidative stress (lower concentration of malondialdehyde, P = 0.023; dose-dependent effect), modulated the inflammatory process (lower concentration of interleukin-10, P<0.001; dose-dependent effect) and decreased the deposit of collagen (lower percentage of interstitial collagen fraction, P<0.001; dose-dependent effect). In conclusion, açai pulp supplementation attenuated cardiac remodeling after myocardial infarction in rats. Also, different doses of açai pulp supplementation have dose-dependent effects on cardiac remodeling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264854PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896726PMC
April 2022

Jaboticaba () Attenuates Ventricular Remodeling after Myocardial Infarction in Rats.

Antioxidants (Basel) 2022 Jan 27;11(2). Epub 2022 Jan 27.

Internal Medicine Department, Botucatu Medical School, São Paulo State University (UNESP), Botucatu 18618-687, Brazil.

The cardiac remodeling after myocardial infarction is characterized by inflammation and oxidative stress. Thus, this study aimed to test the hypothesis that jaboticaba, due to its anti-inflammatory and antioxidants properties, attenuates cardiac remodeling after myocardial infarction. Wistar rats were submitted to myocardial infarction due to coronary artery occlusion, and divided into four experimental groups: C, sham control animals; I, animals submitted to myocardial infarction, received a standard diet; IJ2, animals submitted to myocardial infarction, received a standard diet plus 2% jaboticaba; and IJ4, animals submitted to myocardial infarction, received a standard diet plus 4% jaboticaba. After a three-month follow-up, echocardiography, histology, oxidative stress, and cardiac energy metabolism were analyzed. There was no difference in infarct size or mortality among the infarcted groups. The IJ4 group displayed improved diastolic function, as assessed by isovolumetric relaxation time normalized to the heart rate. As expected, the percentage of collagen was higher in all infarcted groups than in the C group. However, the IJ2 group had less collagen than groups I and IJ4. The IJ4 group presented lower PFK activity than I and IJ2, and lower pyruvate dehydrogenase activity than controls, whereas the IJ2 group showed no differences compared to the control group in both LDH and ATP synthase activity. The 2% and 4% doses attenuated lipid peroxidation and increased the activity of glutathione peroxidase compared with the I group. In conclusion, jaboticaba attenuated the remodeling process after myocardial infarction, which was associated with decreased oxidative stress and improved energy metabolism.
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http://dx.doi.org/10.3390/antiox11020249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868135PMC
January 2022

Vitamin D supplementation alleviates chemically-induced cirrhosis-associated hepatocarcinogenesis.

J Steroid Biochem Mol Biol 2022 01 10;215:106022. Epub 2021 Nov 10.

São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil; São Paulo State University (UNESP), Medical School, Department of Pathology, Botucatu, SP, Brazil. Electronic address:

Vitamin D (VD) deficiency has been associated with increased risk for cirrhosis and hepatocellular carcinoma, a highly incident malignant neoplasia worldwide. On the other hand, VD supplementation has shown some beneficial effects in clinical studies and rodent models of chronic liver disease. However, preventive effects of dietary VD supplementation in cirrhosis-associated hepatocarcinogenesis is still unknow. To investigate this purpose, male Wistar rats submitted to a combined diethylnitrosamine- and thioacetamide-induced model were concomitantly supplemented with VD (5,000 and 10,000 IU/kg diet) for 25 weeks. Liver samples were collected for histological, biochemical and molecular analysis. Serum samples were used to measure 25-hydroxyvitamin D [25(OH)D] and alanine aminotransferase levels. Both VD interventions decreased hepatic collagen deposition and pro-inflammatory p65 protein levels, while increased hepatic antioxidant catalase and glutathione peroxidase activities and serum 25(OH)D, without a clear dose-response effect. Nonetheless, only the highest concentration of VD increased hepatic protein levels of VD receptor, while decreased the number of large preneoplastic glutathione-S-transferase- (>0.5 mm²) and keratin 8/18-positive lesions, as well the multiplicity of hepatocellular adenomas. Moreover, this intervention increased hepatic antioxidant Nrf2 protein levels and glutathione-S-transferase activity. In summary, dietary VD supplementation - in special the highest intervention - showed antifibrotic and antineoplastic properties in chemically-induced cirrhosis-associated hepatocarcinogenesis. The positive modulation of Nrf2 antioxidant axis may be mechanistically involved with these beneficial effects, and may guide future clinical studies.
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http://dx.doi.org/10.1016/j.jsbmb.2021.106022DOI Listing
January 2022

Pera orange (Citrus sinensis) and Moro orange (Citrus sinensis (L.) Osbeck) juices attenuate left ventricular dysfunction and oxidative stress and improve myocardial energy metabolism in acute doxorubicin-induced cardiotoxicity in rats.

Nutrition 2021 Nov-Dec;91-92:111350. Epub 2021 Jun 2.

Internal Medicine Department, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, Brazil.

Objectives: Doxorubicin is a highly effective chemotherapeutic agent for treating several types of cancer; however, it can induce cardiotoxicity. We evaluated the influence of Pera and Moro orange juices on cardiac remodeling induced by acute administration of doxorubicin in rats.

Methods: We allocated 120 male Wistar rats into six groups: control (C), Pera orange juice (PO), Moro orange juice (MO), doxorubicin (D), doxorubicin + Pera orange juice (DPO), and doxorubicin + Moro orange juice (DMO). Groups PO and DPO received Pera orange juice, MO and DMO received Moro orange juice, and C and D received water with maltodextrin (100 g/L) for 4 wk. Subsequently, groups D, DPO, and DMO received 20 mg/kg doxorubicin and C, PO, and MO received saline. Echocardiogram and euthanasia were performed 48 h after doxorubicin injection. Juice and animal-serum flavonoid identification and quantification were evaluated by liquid chromatography/electrospray ionization multistage mass spectrometry. Oxidative stress and myocardial metabolism were evaluated by spectrophotometry.

Results: Systolic and diastolic left ventricular dysfunction increased oxidative stress and pathologic changes in myocardial energy metabolism of rats treated with doxorubicin. Intake of both orange juices improved left ventricular function, decreased oxidative stress, and attenuated the myocardial energy metabolism changes. Moro orange juice had a more pronounced effect than Pera orange juice in glutathione peroxidase activity, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase activity.

Conclusions: Pera and Moro orange juices attenuated cardiac remodeling induced by doxorubicin, improved myocardial energy metabolism, and attenuated oxidative stress. However, Moro orange juice was more effective than Pera orange juice in modifying energy metabolism.
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http://dx.doi.org/10.1016/j.nut.2021.111350DOI Listing
December 2021

Green Tea () Extract Increased Topoisomerase II, Improved Antioxidant Defense, and Attenuated Cardiac Remodeling in an Acute Doxorubicin Toxicity Model.

Oxid Med Cell Longev 2021 5;2021:8898919. Epub 2021 May 5.

Internal Medicine Department, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, Brazil.

Experimental studies have shown the action of green tea in modulating cardiac remodeling. However, the effects of green tea on the cardiac remodeling process induced by doxorubicin (DOX) are not known. Therefore, this study is aimed at evaluating whether green tea extract could attenuate DOX-induced cardiac remodeling, assessed by cardiac morphological and functional changes and associated with the evaluation of different modulators of cardiac remodeling. The animals were divided into four groups: the control group (C), the green tea group (GT), the DOX group (D), and the DOX and green tea group (DGT). Groups C and GT received intraperitoneal sterile saline injections, D and DGT received intraperitoneal injections of DOX, and GT and DGT were fed chow supplemented with green tea extract for 35 days prior to DOX injection. After forty-eight hours, we performed an echocardiogram and euthanasia and collected the materials for analysis. Green tea attenuated DOX-induced cardiotoxicity by increasing cardiac function and decreasing the concentric remodeling. Treatment with DOX increased oxidative stress in the heart, marked by a higher level of lipid hydroperoxide (LH) and lower levels of antioxidant enzymes. Treatment with green tea increased the antioxidant enzymes' activity and decreased the production of LH. Green tea extract increased the expression of Top2- independent of DOX treatment. The activity of ATP synthase, citrate synthase, and complexes I and II decreased with DOX, without the effects of green tea. Both groups that received DOX presented with a lower ratio of P-akt/T-akt and a higher expression of CD45, TNF, and intermediate MMP-2, without the effects of green tea. In conclusion, green tea attenuated cardiac remodeling induced by DOX and was associated with increasing the expression of Top2- and lowering oxidative stress. However, energy metabolism and inflammation probably do not receive the benefits induced by green tea in this model.
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http://dx.doi.org/10.1155/2021/8898919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116148PMC
November 2021

Vitamin D Supplementation Induces Cardiac Remodeling in Rats: Association with Thioredoxin-Interacting Protein and Thioredoxin.

Arq Bras Cardiol 2021 05;116(5):970-978

Faculdade de Medicina de Botucatu - UNESP, Botucatu, SP - Brasil.

Background: Vitamin D (VD) has been shown to play an important role in cardiac function. However, this vitamin exerts a biphasic "dose response" curve in cardiovascular pathophysiology and may cause deleterious effects, even in non-toxic doses. VD exerts its cellular functions by binding to VD receptor. Additionally, it was identified that the thioredoxin-interacting protein (TXNIP) expression is positively regulated by VD. TXNIP modulate different cell signaling pathways that may be important for cardiac remodeling.

Objective: To evaluate whether VD supplementation lead to cardiac remodeling and if TXNIP and thioredoxin (Trx) proteins are associated with the process.

Methods: A total of 250 Male Wistar rats were allocated into three groups: control (C, n=21), with no VD supplementation; VD3 (n = 22) and VD10 (n=21), supplemented with 3,000 and 10,000 IU of VD/ kg of chow respectively, for two months. The groups were compared by one-way analysis of variance (ANOVA) and Holm-Sidak post hoc analysis, (variables with normal distribution), or by Kruskal-Wallis test and Dunn's test post hoc analysis. The significance level for all tests was 5%.

Results: TXNIP protein expression was higher and Trx activity was lower in VD10. The animals supplemented with VD showed increased lipid hydroperoxide and decreased superoxide dismutase and glutathione peroxidase. The protein Bcl-2 was lower in VD10. There was a decrease in fatty acid β-oxidation, tricarboxylic acid cycle and electron transport chain with shift to increase in glycolytic pathway.

Conclusion: VD supplementation led to cardiac remodeling and this process may be modulated by TXNIP and Trx proteins and consequently oxidative stress.
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http://dx.doi.org/10.36660/abc.20190633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121481PMC
May 2021

Beneficial effects of anthocyanin-rich peels of Myrtaceae fruits on chemically-induced liver fibrosis and carcinogenesis in mice.

Food Res Int 2021 01 8;139:109964. Epub 2020 Dec 8.

São Paulo State University (UNESP), Biosciences Institute, Department of Structural and Functional Biology, Botucatu, SP, Brazil. Electronic address:

Hepatocellular carcinoma (HCC) arising from fibrosis/cirrhosis is the most common type of primary liver cancer. Conversely, a higher intake of fruits and vegetables might play a protective role in HCC risk. Recently, Myrtaceae family tropical fruits have raised great interest due to the high levels of anthocyanins especially in their peels, which are usually discarded upon consumption. Anthocyanins are antioxidant pigments known to have beneficial effects in vivo/in vitro cancer bioassays. Thus, we evaluated whether dietary Myrciaria jaboticaba, Syzygium cumini, and Syzygium malaccense fruit peel powders reduce fibrosis and hepatocarcinogenesis in mice. Female C3H/HeJ mice were submitted to the model of diethylnitrosamine/carbon tetrachloride-induced liver fibrosis and carcinogenesis. Concomitantly, mice received a basal diet containing 2% of M. jaboticaba, S. cumini, or S. malaccense fruit peel powders, obtained by convective drying, for 10 weeks. M. jaboticaba peel powder showed the highest levels of total anthocyanins, while S. cumini peel powder displayed the greatest diversity of these pigments. All Myrtaceae family peel powders reduced the serum levels of the liver injury marker alanine aminotransferase. M. jaboticaba peel feeding reduced the incidence of liver preneoplastic foci, hepatocyte proliferation (Ki-67), and the protein levels of hepato-mitogen tumor necrosis factor-alpha (TNF-α). M. jaboticaba peel feeding also diminished liver lipid peroxidation and increased total glutathione levels. S. cumini peel feeding reduced hepatic collagen, lipid peroxidation, and TNF-α levels while increased catalase activity. Although S. malaccense peel powder, which displayed the lowest anthocyanin levels, decreased oxidative stress, and cytokine levels, no effects were observed on liver fibrosis or preneoplastic lesion outcomes. Findings indicate a protective effect of anthocyanin-rich M. jaboticaba and S. cumini peel powder feeding on preneoplastic lesion development and fibrosis, respectively. Results indicate that differential biological responses may be attributed to distinct anthocyanin profiles and levels, assigning a functional/market value to the underutilized peel fraction.
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http://dx.doi.org/10.1016/j.foodres.2020.109964DOI Listing
January 2021

The role of glucose metabolism and insulin resistance in cardiac remodelling induced by cigarette smoke exposure.

J Cell Mol Med 2021 01 9;25(2):1314-1318. Epub 2020 Dec 9.

Department of Internal Medicine, Botucatu Medical School, São Paulo State University-UNESP, Botucatu, Brazil.

The aim of this study is to evaluate whether the alterations in glucose metabolism and insulin resistance are mechanisms presented in cardiac remodelling induced by the toxicity of cigarette smoke. Male Wistar rats were assigned to the control group (C; n = 12) and the cigarette smoke-exposed group (exposed to cigarette smoke over 2 months) (CS; n = 12). Transthoracic echocardiography, blood pressure assessment, serum biochemical analyses for catecholamines and cotinine, energy metabolism enzymes activities assay; HOMA index (homeostatic model assessment); immunohistochemistry; and Western blot for proteins involved in energy metabolism were performed. The CS group presented concentric hypertrophy, systolic and diastolic dysfunction, and higher oxidative stress. It was observed changes in energy metabolism, characterized by a higher HOMA index, lower concentration of GLUT4 (glucose transporter 4) and lower 3-hydroxyl-CoA dehydrogenase activity, suggesting the presence of insulin resistance. Yet, the cardiac glycogen was depleted, phosphofructokinase (PFK) and lactate dehydrogenase (LDH) increased, with normal pyruvate dehydrogenase (PDH) activity. The activity of citrate synthase, mitochondrial complexes and ATP synthase (adenosine triphosphate synthase) decreased and the expression of Sirtuin 1 (SIRT1) increased. In conclusion, exposure to cigarette smoke induces cardiac remodelling and dysfunction. The mitochondrial dysfunction and heart damage induced by cigarette smoke exposure are associated with insulin resistance and glucose metabolism changes.
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http://dx.doi.org/10.1111/jcmm.16053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812248PMC
January 2021

Impact of Modality and Intensity of Early Exercise Training on Ventricular Remodeling after Myocardial Infarction.

Oxid Med Cell Longev 2020 20;2020:5041791. Epub 2020 Jul 20.

Internal Medicine Department, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, Brazil.

The objective of this study was to analyze the impact of different modalities and intensities of exercise training on cardiac remodeling started early after experimental myocardial infarction (MI). Male Wistar rats, weighing 200-250 g, were subjected to experimental MI. After 5 days, the animals were allocated into three experimental groups and observed for three months: S (sedentary control animals), C (animals subjected to continuous low-intensity training), and HIT (animals subjected to high-intensity interval training). Low-intensity exercise training was performed at a treadmill speed corresponding to 40% VO max, which was kept unchanged throughout the entire session (i.e., continuous low-intensity training). High-intensity interval training was performed in such a way that rats run during 3 min at 60% VO max, followed by 4-minute intervals at 85% VO max (i.e., high-intensity interval training). After the follow-up period, we studied hypertrophy and ventricular geometry, functional alterations and , oxidative stress, apoptosis, and cardiac energetic metabolism. Our data showed that both high-intensity interval and continuous low-intensity modalities improved cardiac energetic metabolism variables in comparison with sedentary infarcted animals. In addition, high-intensity interval training decreased cardiac oxidative stress, associated with improved diastolic function. On the other hand, the continuous low-intensity group showed impairment of cardiac function. Therefore, altogether, our data suggest that high-intensity interval training could be the best modality for early physical exercise after MI and should be better studied in this clinical scenario.
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http://dx.doi.org/10.1155/2020/5041791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387991PMC
May 2021

Spondias mombin L. attenuates ventricular remodelling after myocardial infarction associated with oxidative stress and inflammatory modulation.

J Cell Mol Med 2020 07 29;24(14):7862-7872. Epub 2020 May 29.

Internal Medicine Department, Botucatu Medical School, São Paulo State University (UNESP), Botucatu, Brazil.

The objective of this study was to evaluate Spondias mombin L. (SM) pulp and its influence on cardiac remodelling after myocardial infarction (MI). Male Wistar rats were assigned to four groups: a sham group (animals underwent simulated surgery) that received standard chow (S; n = 20), an infarcted group that received standard chow (MI; n = 24), an infarcted group supplemented with 100 mg of SM/kg bodyweight/d, (MIS100; n = 23) and an infarcted group supplemented with 250 mg of SM/kg bodyweight/d (MIS250; n = 22). After 3 months of treatment, morphological, functional and biochemical analyses were performed. MI induced structural and functional changes in the left ventricle with worsening systolic and diastolic function, and SM supplementation at different doses did not influence these variables as analysed by echocardiography and an isolated heart study (P > .05). However, SM supplementation attenuated cardiac remodelling after MI, reducing fibrosis (P = .047) and hypertrophy (P = .006). Biomarkers of oxidative stress, inflammatory processes and energy metabolism were further investigated in the myocardial tissue. SM supplementation improved the efficiency of energy metabolism and decreased lipid hydroperoxide in the myocardium [group S (n = 8): 267.26 ± 20.7; group MI (n = 8): 330.14 ± 47.3; group MIS100 (n = 8): 313.8 ± 46.2; group MIS250: 294.3 ± 38.0 nmol/mg tissue; P = .032], as well as decreased the activation of the inflammatory pathway after MI. In conclusion, SM supplementation attenuated cardiac remodelling processes after MI. We also found that energy metabolism, oxidative stress and inflammation are associated with this effect. In addition, SM supplementation at the highest dose is more effective.
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http://dx.doi.org/10.1111/jcmm.15419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348186PMC
July 2020

Protective Effects of Dietary Capsaicin on the Initiation Step of a Two-Stage Hepatocarcinogenesis Rat Model.

Nutr Cancer 2021 13;73(5):817-828. Epub 2020 May 13.

Department of Morphology, Biosciences Institute, São Paulo State University (UNESP), Botucatu, SP, Brazil.

Capsaicin (CPS), an ingredient of plants, has anti-inflammatory, antioxidant and antitumoral properties. The mechanisms of CPS on hepatocarcinogenesis preclinical bioassays are not described. Thus, the protective effects CPS were evaluated in the early stages of chemically-induced hepatocarcinogenesis. Male Wistar rats received diet containing 0.01% or 0.02% CPS for 3 weeks. Afterwards, animals received a dose of hepatocarcinogen diethylnitrosamine (DEN, 100 mg/kg body weight). From weeks 4-12, groups had their diet replaced by a 0.05% phenobarbital supplemented one to promote DEN-induced preneoplastic lesions. Animals were euthanized 24 h after DEN administration ( = 5/group) or at week 12 ( = 9/group). The estimated CPS intake in rats resembled human consumption. At the end of week 3, dietary 0.02% CPS attenuated DEN-induced oxidative damage and, consequently, hepatocyte necrosis by reducing serum alanine aminotransferase levels, liver CD68-positive macrophages, lipid peroxidation, while increasing antioxidant glutathione system. Additionally, 0.02% CPS upregulated vanilloid receptor and anti-inflammatory epoxygenase genes in the liver. Ultimately, previous 0.02% CPS intake decreased the number of GST-P-positive preneoplastic lesions at week 12. Thus, CPS attenuated preneoplastic lesion development, primarily by diminishing DEN-induced oxidative liver injury. Findings indicate that CPS is a promising chemopreventive agent when administered after and during the early stages of hepatocarcinogenesis.
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http://dx.doi.org/10.1080/01635581.2020.1764067DOI Listing
August 2021

Calcitriol Prevents Neuroinflammation and Reduces Blood-Brain Barrier Disruption and Local Macrophage/Microglia Activation.

Front Pharmacol 2020 12;11:161. Epub 2020 Mar 12.

Department of Microbiology and Immunology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, Brazil.

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that involves damage to the myelin sheath surrounding axons. MS therapy is based on immunomodulatory drugs that reduce disease recurrence and severity. Vitamin D is a hormone whose immunomodulatory ability has been widely demonstrated, including in experimental autoimmune encephalomyelitis (EAE), which is an animal model of CNS inflammation. In this study, we evaluated the potential of very early intervention with the active form of vitamin D (1,25-dihydroxyvitamin D3) to control neuroinflammation during EAE development. EAE was induced in C57BL/6J mice and 1,25-dihydroxyvitamin D3 administration began 1 day after disease induction. This procedure decreased prevalence, clinical score, inflammation, and demyelination. It also reduced MHCII expression in macrophages and microglia as well as the level of oxidative stress and messenger RNA (mRNA) expression for , , at the CNS. Otherwise, mRNA expression for increased at the lumbar spinal cord. These effects were accompanied by the stabilization of blood-spinal cord barrier permeability. The results of this study indicate that early intervention with 1,25-dihydroxyvitamin D3 can control the neuroinflammatory process that is the hallmark of EAE and MS immunopathogenesis and should thus be explored as an adjunct therapy for MS patients.
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http://dx.doi.org/10.3389/fphar.2020.00161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080989PMC
March 2020

30 Years of Experience with Non-Hodgkin Lymphoma in Children and Adolescents: a retrospective cohort study.

Rev Assoc Med Bras (1992) 2020 27;66(1):25-30. Epub 2020 Feb 27.

. Divisão de Hematologia Pediátrica, Departamento de Pediatria, Escola de Medicina, Universidade Federal de Minas Gerais,Belo Horizonte, MG, Brasil.

Objective: Describe the clinical and demographic characteristics of pediatric patients with non-Hodgkin's lymphoma (NHL) enrolled in a tertiary unit of Pediatric Hematology between 1982-2015.

Patients And Methods: A retrospective cohort study of 140 patients aged 16 years or less with NHL. Demographic characteristics, data on diagnosis, and outcomes were analyzed. The overall survival (OS) analysis and stratification by the most frequent histological subtypes were performed using the Kaplan-Meier method.

Results: One hundred and thirty-six patients with de novo NHL and four with NHL as a second malignancy were analyzed. The median age at diagnosis was 6.4 years (interquartile range, 4.2 to 11.1 years); 101 patients were males. Four patients had primary immunodeficiency, four had human immunodeficiency virus, two post-liver transplantation, and one had autoimmune lymphoproliferative syndrome. The most frequent histological type was NHL of mature B- cell (B-NHL-B; 67.1%), with Burkitt's lymphoma being the most frequent subtype, and lymphoblastic lymphoma (LBL, 21.4%). The main clinical manifestation at the diagnosis was abdominal tumors (41.4%). During the follow-up time, 13 patients relapsed, but five of them reached a second remission. Thirty-five patients died, and 103 remained alive in clinical remission. No contact was possible for two patients. The OS at 5 years was 74.5% (± 3.8%). The OS estimated for patients with LBL, NHL-B, and the remaining was 80.4%±7.9%, 72.8%±4.7%, and 74.5%±11%, respectively (P = 0.58).

Conclusion: Our results are comparable with cohorts from other middle-income countries.
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http://dx.doi.org/10.1590/1806-9282.66.1.25DOI Listing
April 2020

Proteomic analysis and antibacterial resistance mechanisms of Salmonella Enteritidis submitted to the inhibitory effect of Origanum vulgare essential oil, thymol and carvacrol.

J Proteomics 2020 03 24;214:103625. Epub 2019 Dec 24.

Department of Microbiology and Immunology, Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil.

Biological properties of natural products are an important research target and essential oils (EO) from aromatic plants with antimicrobial properties are well documented. However, their uses are limited, and the mechanisms underlying their antibacterial activity are still not well known. Therefore, our objective was to evaluate the antibacterial activities of Origanum vulgare EO, thymol and carvacrol against Salmonella Enteritidis ATCC 13076 strain, particularly regarding the bacterial proteic profile, enzymatic activities and DNA synthesis. Bacterial expressed proteins were evaluated using an untreated assay control and treatments with sublethal concentrations of oregano EO, carvacrol and thymol. The same protein extracts were also assayed for oxidative stress and energy metabolism enzyme activities, as well as effect on DNA synthesis. Protein expression outcomes revealed by 2D-SDS-PAGE, from antimicrobial actions, showed a stress response with differential expressions of chaperones and cellular protein synthesis mediated by the bacterial signaling system. In addition, Salmonella used a similar mechanism in defense against oxidative stress, for its survival. Thus, the antibacterial inhibitory activity of EO was preferentially associated with the presence of thymol and there was interference in protein regulation as well as DNA synthesis affected by these compounds. SIGNIFICANCE: Antimicrobial activity of essential oils (EO) is already known. In this way, the understanding of how this activity occurs is a fundamental part to provide the practical and rational use of these substances. In the current scenario, where the emergence of resistant bacteria or even multiresistant bacteria against conventional antimicrobials, the search for alternatives becomes essential, since the discovery of new inhibitory substances does not occur at the same speed. The anti-Salmonella action allied to the knowledge about the biological processes affected by O. vulgare EO contribute to these bioactive compounds being effectively used as agents in the safety and shelf life of food in a future product, packaging or process where the antibacterial activity is safe and best used.
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http://dx.doi.org/10.1016/j.jprot.2019.103625DOI Listing
March 2020

Euterpe Oleracea Mart. (Açaí) Reduces Oxidative Stress and Improves Energetic Metabolism in Myocardial Ischemia-Reperfusion Injury in Rats.

Arq Bras Cardiol 2020 01;114(1):78-86

Universidade Estadual Paulista Júlio de Mesquita Filho - UNESP, São Paulo, SP - Brazil.

Background: Euterpe oleracea Mart. (açaí) is a fruit with high antioxidant capacity and could be an adjuvant strategy to attenuate ischemia-reperfusion injury.

Objective: To evaluate the influence of açaí in global ischemia-reperfusion model in rats.

Methods: Wistar rats were assigned to 2 groups: Control (C: receiving standard chow; n = 9) and Açaí (A: receiving standard chow supplemented with 5% açaí; n = 10). After six weeks, the animals were subjected to the global ischemia-reperfusion protocol and an isolated heart study to evaluate left ventricular function. Level of significance adopted: 5%.

Results: There was no difference between the groups in initial body weight, final body weight and daily feed intake. Group A presented lower lipid hydroperoxide myocardial concentration and higher catalase activity, superoxide dismutase and glutathione peroxidase than group C. We also observed increased myocardial activity of b-hydroxyacyl coenzyme-A dehydrogenase, pyruvate dehydrogenase, citrate synthase, complex I, complex II and ATP synthase in the A group as well as lower activity of the lactate dehydrogenase and phosphofructokinase enzymes. The systolic function was similar between the groups, and the A group presented poorer diastolic function than the C group. We did not observe any difference between the groups in relation to myocardial infarction area, total and phosphorylated NF-kB, total and acetylated FOXO1, SIRT1 and Nrf-2 protein expression.

Conclusion: despite improving energy metabolism and attenuating oxidative stress, açai supplementation did not decrease the infarcted area or improve left ventricular function in the global ischemia-reperfusion model.
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http://dx.doi.org/10.36660/abc.20180140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025309PMC
January 2020

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

Neurotherapeutics 2020 01;17(1):218-234

Department of Microbiology and Immunology, Institute of Biosciences, São Paulo State University (UNESP), Rua Dr. Plinio Pinto e Silva, S/N, Distrito de Rubião Júnior, Botucatu, São Paulo, 18618-691, Brazil.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG and the animals were injected daily with Ket from the seventh to the 17th day after disease induction. This early intervention with Ket significantly reduced disease prevalence and severity. The protective effect was concomitant with less NLRP3 inflammasome activation, rebalanced oxidative stress and also reduced T cell infiltration at the CNS. Even though Ket administration did not alter mast cell percentage at the CNS, it decreased the local CPA3 and CMA1 mRNA expression that are enzymes typically produced by these cells. Evaluation of the CNS-barrier permeability indicated that Ket clearly restored the permeability levels of this barrier. Ket also triggered an evident lymphadenomegaly due to accumulation of T cells that produced higher levels of encephalitogenic cytokines in response to in vitro stimulation with MOG. Altogether these findings reinforce the concept that mast cells are particularly relevant in MS immunopathogenesis and that Ket, a known stabilizer of their activity, has the potential to be used in MS control.
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http://dx.doi.org/10.1007/s13311-019-00775-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007452PMC
January 2020

Euterpe oleracea Mart. (Açai) Supplementation Attenuates Acute Doxorubicin-Induced Cardiotoxicity in Rats.

Cell Physiol Biochem 2019 ;53(2):388-399

Medical School, São Paulo State University (Unesp), Botucatu, Brazil,

Background/aims: Doxorubicin, a chemotherapy drug used successfully for years, could induce cardiotoxicity. Euterpe oleracea Mart. (açai) is a fruit high in antioxidant properties. The aim of this study was to evaluate doxorubicin-induced cardiotoxicity prevention after açai administration.

Methods: A total of 64 male Wistar rats were allocated into 4 groups: control (C), açai (A), doxorubicin (D) and açai-doxorubicin (DA). Rats received regular chow (C and D groups) or chow supplemented with açai 5% (A and DA groups) for 4 weeks. Subsequently, rats received doxorubicin 20 mg/kg (D and DA groups) or saline (C and A groups). Euthanasia was performed 48 hours after doxorubicin injection. Left ventricular function was evaluated by echocardiography in vivo and by isolated heart study ex vivo. Oxidative stress, myocardial metabolism and nitric oxide metabolite were evaluated by spectrophotometry, MMP-2 activity by zymography and caspase-3 and Bcl-2 protein expression by Western blot.

Results: Doxorubicin induced decreases in body weight, food and water ingestion. We observed decreases in left ventricular fractional shortening in rats treated with doxorubicin. Additionally, the same rats showed lower +dP/dt and -dP/dt during isolated heart study than those who did not receive doxorubicin. Doxorubicin injection increased caspase-3 protein expression, myocardium lipid hydroperoxide concentration, MMP-2 activity, phosphofructokinase and lactate dehydrogenase activity, and decreased β-hydroxyacyl-CoA dehydrogenase, pyruvate dehydrogenase, citrate synthase, complex I, complex II and ATP synthase activity in myocardium. Açai supplementation improved left ventricular fractional shortening, decreased myocardium lipid hydroperoxide concentration, MMP-2 activity, and improved β-hydroxyacyl-CoA dehydrogenase, phosphofructokinase, citrate synthase, complex II and ATP synthase enzymatic activities. We did not observe differences in nitric oxide metabolite concentrations between groups.

Conclusion: Doxorubicin induced left ventricular dysfunction, increases in oxidative stress, changes in myocardium metabolism and MMP-2 activation. Açai supplementation was able to prevent these alterations.
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http://dx.doi.org/10.33594/000000145DOI Listing
August 2019

Comparative Proteomics of Methicillin-Resistant Subjected to Synergistic Effects of the Lantibiotic Nisin and Oxacillin.

Microb Drug Resist 2020 Mar 25;26(3):179-189. Epub 2019 Jun 25.

Department of Microbiology and Immunology, Institute of Biosciences of Botucatu (IBB), São Paulo State University (UNESP), Botucatu, Brazil.

We investigated the responses and mechanisms of action of methicillin-resistant (MRSA) metabolism when exposed under sublethal concentrations of the synergistic antibacterial combination of nisin + oxacillin (¼ of maximum sublethal concentration) and sublethal concentrations of oxacillin only and nisin only. A total of 135 proteins were identified, showing an alteration in the expression of 85 proteins when treatment was compared with untreated bacteria (control). When the bacteria were treated using the combination, there was an increase in the expression of proteins related to resistance (., beta-lactamase) and also in the ones involved in protein synthesis, and there was a decrease in the expression of proteins related to stress and alterations in proteins related to bacterial energy metabolism. Bacterial oxidative stress showed that the combination was able to induce oxidative stress ( < 0.05) and increase enzyme activities and lipid hydroperoxide levels compared with individual treatments. The analysis of cell ultrastructure showed damage in MRSA, especially on the bacterial wall and the plasma membrane, with cell lysis and death. Thus, the changes caused by these treatments affected different proteins related to the bacterial biological processes and signaling pathways such as cell division, structure, stress, regulation, bacterial resistance, protein synthesis, gene expression, energetic metabolism, and virulence. It was observed that synergism among antimicrobials has high potential in therapeutic use and may reduce the required amounts of antibacterial substances in addition to being effective on different targets in bacterial cells.
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http://dx.doi.org/10.1089/mdr.2019.0038DOI Listing
March 2020

The combination of resveratrol and exercise enhances muscle growth characteristics in pacu (Piaractus mesopotamicus).

Comp Biochem Physiol A Mol Integr Physiol 2019 09 8;235:46-55. Epub 2019 May 8.

Department of Morphology, Institute of Bioscience, Sao Paulo State University, UNESP, Botucatu, SP, Brazil; Aquaculture Center, CAUNESP, Sao Paulo State University, UNESP, Jaboticabal, SP, Brazil. Electronic address:

Pacu is a tropical fish with important value to aquaculture. During cellular metabolism, reactive oxygen species (ROS) are produced, which can influence muscle growth. Resveratrol is an effective antioxidant that scavenges ROS and can modulate physical performance preventing oxidative stress. We investigated the effects of resveratrol and exercise on pacu muscle growth characteristics. Four groups were used: fish fed with control diet /without exercise (C); fish fed with control diet/subjected to exercise (CE); fish fed resveratrol-supplemented diet/without exercise (R); and fish fed resveratrol-supplemented diet/subjected to exercise (RE). At 30 days, the RE group presented a significant increase in body weight, fewer muscle fibers in the 20-40 μm and more fibers in the >60 μm diameter class compared to the C group. At day 7, catalase activity decreased in CE and RE groups. Superoxide dismutase activity decreased only in the CE group. Myod and mtor gene expression was higher in R and RE and igf-1 was up-regulated in the RE group. Murf1a level decreased in CE, R, and RE, while sdha expression was higher in the RE group. We suggest that resveratrol in combination with exercise was beneficial for muscle growth and metabolism, increasing the expression levels of genes related to muscle anabolism and oxidative metabolism, besides the decrease of catabolic gene expression. Notably, all of these changes occurred together with muscle hypertrophy and increased body weight. Our results show a positive application for resveratrol in association with exercise as a strategy to improve the growth performance of juvenile pacus.
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http://dx.doi.org/10.1016/j.cbpa.2019.05.002DOI Listing
September 2019

Panax ginseng methabolit (GIM-1) prevents oxidative stress and apoptosis in human Sertoli cells exposed to Monobutyl-phthalate (MBP).

Reprod Toxicol 2019 06 6;86:68-75. Epub 2019 Apr 6.

São Paulo State University (UNESP), Institute of Biosciences, Department of Morphology, Botucatu, SP, 18618-689, Brazil. Electronic address:

This study evaluated oxidative stress markers in Human Sertoli cells cultivated on Geltrex® and exposed to Monobutyl Phthalate (MBP), and the potential cytoprotective role of GIM-1 on the antioxidant response. Exposure was performed at 30 min, 1, 12 and 48 h into 4 groups: control, MBP (10μM), GIM-1 (0,05μM) and MBP + GIM-1. Morphology was evaluated. Antioxidant enzymes were analyzed by colorimetric method; NRF-2, SIRT-1, 8- OHdG and Cleaved Caspase-3 by Western Blot. Larger spaces between cells were shown in MBP treatment; GIM-1 was similar to Control and MBP + GIM-1 showed an intermediate aspect. MBP reduced enzymatic activity of all enzymes and NRF-2 expression, increasing cleaved Caspase-3 expression; while GIM-1 increased antioxidants markers alone and attenuated MPB effects in MBP + GIM-1. MBP induced deleterious effects on Sertoli cells, increasing the oxidative stress, apoptosis and modifying their distribution in culture; however, GIM-1 acted as an important cytoprotective agent reversing our attenuating MBP effects.
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http://dx.doi.org/10.1016/j.reprotox.2019.02.008DOI Listing
June 2019

Lipid damage is the best marker of oxidative injury during the cardiac remodeling process induced by tobacco smoke.

BMC Pharmacol Toxicol 2018 Nov 16;19(1):74. Epub 2018 Nov 16.

Internal Medicine Department, Botucatu Medical School, UNESP - São Paulo State University, Botucatu, Brazil.

Background: Oxidative stress is one potential mechanism that explain the direct effects of smoking on cardiac remodeling process. However, no study has compared different myocardial products of macromolecule oxidation after tobacco smoke exposure. Thus, the aim of this study was to investigate the lipid hydroperoxide (LH) levels, protein carbonyl concentrations and DNA damage in cardiac tissue of rats exposed to tobacco smoke.

Methods: Male Wistar rats were divided into two groups: group C (control, n = 14) composed of animals not exposed to cigarette smoke; group ETS (exposed to tobacco smoke, n = 14) composed by animals exposed to cigarette smoke. The animals were exposed to 2 month of ETS and morphological, biochemical and functional analyses were performed.

Results: Cardiac cotinine levels were elevated in the ETS group. In addition, the myocyte cross-sectional area was higher in the ETS group. (C = 266.6 ± 23.2 μm and ETS = 347.5 ± 15.1 μm, p <  0.001). Cardiac LH was higher in the ETS group than in group C (C = 196.4 ± 51.5 nmol/g and ETS = 331.9 ± 52.9 nmol/g, p <  0.001). However, there were no between-group differences in cardiac protein carbonyl concentration or DNA damage.

Conclusions: Therefore, our results suggest that, in this model, lipid damage is a good marker of oxidative damage during the cardiac remodeling process induced by 2 months of exposure to tobacco smoke.
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http://dx.doi.org/10.1186/s40360-018-0268-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240305PMC
November 2018

Zinc Supplementation Attenuates Cardiac Remodeling After Experimental Myocardial Infarction.

Cell Physiol Biochem 2018 4;50(1):353-362. Epub 2018 Oct 4.

São Paulo State University (Unesp), Botucatu Medical School, Internal Medicine Department, Botucatu, Brazil.

Background/aims: The objective of our study was to evaluate the effects of zinc supplementation on cardiac remodeling following acute myocardial infarction in rats.

Methods: Animals were subdivided into 4 groups and observed for 3 months: 1) Sham Control; 2) Sham Zinc: Sham animals receiving zinc supplementation; 3) Infarction Control; 4) Infarction Zinc. After the followup period, we studied hypertrophy and ventricular geometry, functional alterations in vivo and in vitro, changes related to collagen, oxidative stress, and inflammation, assessed by echocardiogram, isolated heart study, western blot, flow cytometer, morphometry, and spectrophotometry.

Results: Infarction induced a significant worsening of the functional variables. On the other hand, zinc attenuated both systolic and diastolic cardiac dysfunction induced by infarction. Considering the infarct size, there was no difference between the groups. Catalase and superoxide dismutase decreased in infarcted animals, and zinc increased its activity. We found higher expression of collagens I and III in infarcted animals, but there was no effect of zinc supplementation. Likewise, infarcted animals had higher levels of IL-10, but without zinc interference. Nrf-2 values were not different among the groups. Infarction increased the amount of Treg cells in the spleen as well as the amount of total lymphocytes. Zinc increased the amount of CD4+ in infarcted animals, but we did not observe effects in relation to Treg cells.

Conclusion: zinc attenuates cardiac remodeling after infarction in rats; this effect is associated with modulation of antioxidant enzymes, but without the involvement of collagens I and III, Nrf-2, IL-10, and Treg cells.
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http://dx.doi.org/10.1159/000494011DOI Listing
November 2018

Fibrosis-associated hepatocarcinogenesis revisited: Establishing standard medium-term chemically-induced male and female models.

PLoS One 2018 13;13(9):e0203879. Epub 2018 Sep 13.

Department of Morphology, Biosciences Institute, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.

Hepatocellular carcinoma causes ~10% of all cancer-related deaths worldwide, usually emerging in a background of liver fibrosis/cirrhosis (70%-90% of cases). Chemically-induced mouse models for fibrosis-associated hepatocarcinogenesis are widely-applied, resembling the corresponding human disease. Nonetheless, a long time is necessary for the development of preneoplastic/neoplastic lesions. Thus, we proposed an early fibrosis-associated hepatocarcinogenesis model for male and female mice separately, focusing on reducing the experimental time for preneoplastic/neoplastic lesions development and establishing standard models for both sexes. Then, two-week old susceptible C3H/HeJ male and female mice (n = 8 animals/sex/group) received a single dose of diethylnitrosamine (DEN, 10 or 50 mg/Kg). During 2 months, mice received 3 weekly doses of carbon tetrachloride (CCl4, 10% corn oil solution, 0.25 to 1.50 μL/g b.wt.) and they were euthanized at week 17. DEN/CCl4 protocols for males and females displayed clear liver fibrosis, featuring collagen accumulation and hepatic stellate cell activation (α-SMA). In addition, liver from males displayed increased CD68+ macrophage number, COX-2 protein expression and IL-6 levels. The DEN/CCl4 models in both sexes impaired antioxidant defense as well as enhanced hepatocyte proliferation and apoptosis. Moreover, DEN/CCl4-treated male and female developed multiple preneoplastic altered hepatocyte foci and hepatocellular adenomas. As expected, the models showed clear male bias. Therefore, we established standard and suitable fibrosis-associated hepatocarcinogenesis models for male and female mice, shortening the experimental time for the development of hepatocellular preneoplastic/neoplastic lesions in comparison to other classical models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203879PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136798PMC
March 2019

Erythrocyte SOD1 activity, but not SOD1 polymorphisms, is associated with ICU mortality in patients with septic shock.

Free Radic Biol Med 2018 08 12;124:199-204. Epub 2018 Jun 12.

Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista, Botucatu, Brazil. Electronic address:

The objective of our study was to evaluate the influence of the superoxide dismutase 1 (SOD1) polymorphisms on erythrocyte SOD1 activity and the mortality of patients with septic shock. We prospectively evaluated 175 patients aged over 18 years with septic shock upon ICU admission. However, 38 patients were excluded. Thus, 137 patients were enrolled in the study. Blood samples were taken within the first 24 h of the patient's admission to determine erythrocyte SOD1 activity and nine SOD1 gene polymorphisms. The mean patient age was 63 ± 16 years, 58% were men, and ICU mortality rate was 66%. The patients who died were older and more severely ill, with higher Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, as well as higher lactate, urea, and protein carbonyl levels. In the logistic regression model, erythrocyte SOD1 activity was associated with ICU mortality. This relationship was also maintained in the highest tertile of SOD1 activity (odds ratio [OR]: 0.02; 95% confidence interval [CI]: 0.00-0.78; p = 0.037). Only SNP rs2070424 of the SOD1 gene influenced erythrocyte SOD1 activity. For patients with the AA allele, the activity of SOD1 was lower in relation to G-carriers (A/G+G/G genotype) (p = 0.019). None of the nine SOD1 SNPs were associated with ICU mortality. In conclusion, the SNP rs2070424 of the SOD1 gene interferes with erythrocyte SOD1 activity, and higher activity of SOD1 was associated with decreased mortality in patients with septic shock.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.013DOI Listing
August 2018

Spondias mombin supplementation attenuated cardiac remodelling process induced by tobacco smoke.

J Cell Mol Med 2018 Aug 29;22(8):3996-4004. Epub 2018 May 29.

Internal Medicine Department, Botucatu Medical School, UNESP-São Paulo State University, Botucatu, Brazil.

The objective of this study was to investigate the influence of Spondias mombin (SM) supplementation on the cardiac remodelling process induced by exposure to tobacco smoke (ETS) in rats. Male Wistar rats were divided into 4 groups: group C (control, n = 20) comprised animals not exposed to cigarette smoke and received standard chow; group ETS (n = 20) comprised animals exposed to cigarette smoke and received standard chow; group ETS100 (n = 20) received standard chow supplemented with 100 mg/kg body weight/d of SM; and group ETS250 (n = 20) received standard chow supplemented with 250 mg/kg body weight/d of SM. The observation period was 2 months. The ETS animals had higher values of left cardiac chamber diameters and of left ventricular mass index. SM supplementation attenuated these changes. In addition, the myocyte cross-sectional area (CSA) was lower in group C compared with the ETS groups; however, the ETS250 group had lower values of CSA compared with the ETS group. The ETS group also showed higher cardiac levels of lipid hydroperoxide (LH) compared with group C; and, groups ETS100 and ETS250 had lower concentrations of LH compared with the ETS group. Regarding energy metabolism, SM supplementation decreased glycolysis and increased the β-oxidation and the oxidative phosphorylation. There were no differences in the expression of Nrf-2, SIRT-1, NF-κB, interferon-gamma and interleukin 10. In conclusion, our results suggest that ETS induced the cardiac remodelling process. In addition, SM supplementation attenuated this process, along with oxidative stress reduction and energy metabolism modulation.
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http://dx.doi.org/10.1111/jcmm.13683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050477PMC
August 2018

Effect of N-Acetylcysteine on Dyslipidemia and Carbohydrate Metabolism in STZ-Induced Diabetic Rats.

Int J Vasc Med 2018 28;2018:6428630. Epub 2018 Jan 28.

Department of Chemistry and Biochemistry, Institute of Biosciences of Botucatu, Sao Paulo State University (UNESP), Rua Professor Doutor Antônio Celso Wagner Zanin s/n, Distrito de Rubião Júnior, 18618-689 Botucatu, SP, Brazil.

Background: Type 1 diabetes mellitus (T1DM) is characterized by insulin-deficient production leading to hyperglycemia, which is associated with diabetic complications such as cardiovascular diseases. Antioxidants have been proving a good alternative to diabetic complications, with N-acetylcysteine (NAC) having antioxidant characteristics. The aim of this study was to assess the effect of NAC on the lipid profile and the atherogenic index (AI) in streptozotocin- (STZ-) induced diabetic rats.

Method: 32 male Wistar rats (60 days of age) weighting ±250 g were randomly distributed into four groups ( = 8): CTRL: control rats; CTRL+NAC: control rats treated with NAC; DM: diabetic rats; DM+NAC: diabetic rats treated with NAC. T1DM was induced using STZ (60 mg/kg, ip; single dose), and NAC (25 mg/kg/day) was administrated by gavage, for 37 days. The animals received chow and water . After the experimental period, blood and cardiac tissue samples were collected to analyze energetic metabolism, lipid profile, and AI.

Results: NAC decreased ( < 0.01) glycemia, energy intake, carbohydrate, and protein consumption in diabetic rats (DM+NAC), when compared with DM, while the alimentary efficiency was improved ( < 0.01) in treated diabetic rats (DM+NAC). Diabetic rats treated with NAC decreased ( < 0.01) lipid profile and AI in diabetic rats (DM+NAC) when compared to DM.

Conclusion: NAC improves lipid profile and decreases AI in STZ-induced diabetic rats.
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http://dx.doi.org/10.1155/2018/6428630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896413PMC
January 2018

Beneficial effects of N-acetylcysteine on hepatic oxidative stress in streptozotocin-induced diabetic rats.

Can J Physiol Pharmacol 2018 Apr 29;96(4):412-418. Epub 2018 Jan 29.

Department of Chemistry and Biochemistry, São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Brazil 18618-970.

Diabetes is one of the leading diseases worldwide and, thus, finding new therapeutic alternatives is essential. The development of non-alcoholic fatty liver disease is a notable diabetic complication. Therefore, antioxidant therapy became a leading topic in the world of diabetes research. The objective of this present study was to evaluate the effects of antioxidant N-acetylcysteine (NAC) administration on serum biochemical parameters and oxidative stress parameters in hepatic tissue of the diabetic rats. Thirty-two animals were divided in 4 groups (n = 8): G1, normal rats; G2, normal rats + NAC; G3, diabetic rats; and G4, diabetic rats + NAC. Diabetes was induced in diabetic groups through streptozotocin. NAC administration was effective in improving hyperglycemia and hypoinsulinemia, as well as reducing serum alanine-aminotransferase and urea, hepatic triglycerides accumulation, and oxidative stress biomarkers in the diabetic liver, as well as improving the activity of hepatic antioxidant enzymes. This effect was likely due to NAC's ability of restoring intracellular glutathione, an important compound for the antioxidant defense, as well as due to NAC's direct antioxidant properties. Thus, NAC administration was useful for reducing hepatic oxidative stress and decreased the deposit of triacylglycerols, minimizing diabetic hepatic damage, making it a promising therapeutic adjuvant in the future.
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http://dx.doi.org/10.1139/cjpp-2017-0559DOI Listing
April 2018

Protein carbonyl concentration as a biomarker for development and mortality in sepsis-induced acute kidney injury.

Biosci Rep 2018 02 25;38(1). Epub 2018 Jan 25.

Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista, Botucatu, Brazil

The objective of the present study was to evaluate protein carbonyl concentration as a predictor of AKI development in patients with septic shock and of renal replacement therapy (RRT) and mortality in patients with SAKI. This was a prospective observational study of 175 consecutive patients over the age of 18 years with septic shock upon Intensive Care Unit (ICU) admission. After exclusion of 46 patients (27 due to AKI at ICU admission), a total of 129 patients were enrolled in the study. Demographic information and blood samples were taken within the first 24 h of the patient's admission to determine serum protein carbonyl concentrations. Among the patients who developed SAKI, the development of AKI was evaluated, along with mortality and need for RRT. The mean age of the patients was 63.3 ± 15.7 years, 47% were male and 51.2% developed SAKI during ICU stay. In addition, protein carbonyl concentration was shown to be associated with SAKI. Among 66 patients with SAKI, 77% died during the ICU stay. Protein carbonyl concentration was not associated with RRT in patients with SAKI. However, the ROC curve analysis revealed that higher levels of protein carbonyl were associated with mortality in these patients. In logistic regression models, protein carbonyl level was associated with SAKI development (OR: 1.416; 95% CI: 1.247-1.609; <0.001) and mortality when adjusted by age, gender, and APACHE II score (OR: 1.357; 95% CI: 1.147-1.605; <0.001). In conclusion, protein carbonyl concentration is predictive of AKI development and mortality in patients with SAKI, with excellent reliability.
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http://dx.doi.org/10.1042/BSR20171238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784177PMC
February 2018

Cardiac Remodeling Induced by All-Trans Retinoic Acid is Detrimental in Normal Rats.

Cell Physiol Biochem 2017 11;43(4):1449-1459. Epub 2017 Oct 11.

São Paulo State University (Unesp), Botucatu Medical School, Internal Medicine Department, Botucatu, Brazil.

Background/aims: This study aimed to discern whether the cardiac alterations caused by retinoic acid (RA) in normal adult rats are physiologic or pathologic.

Methods And Results: Wistar rats were assigned into four groups: control animals (C, n = 20) received a standard rat chow; animals fed a diet supplemented with 0.3 mg/kg/day all-trans-RA (AR1, n = 20); animals fed a diet supplemented with 5 mg/kg/day all-trans-RA (AR2, n = 20); and animals fed a diet supplemented with 10 mg/kg/day all-trans-RA (AR3, n = 20). After 2 months, the animals were submitted to echocardiogram, isolated heart study, histology, energy metabolism status, oxidative stress condition, and the signaling pathway involved in the cardiac remodeling induced by RA. RA increased myocyte cross-sectional area in a dose-dependent manner. The treatment did not change the morphological and functional variables, assessed by echocardiogram and isolated heart study. In contrast, RA changed catalases, superoxide dismutase, and glutathione peroxidases and was associated with increased values of lipid hydroperoxide, suggesting oxidative stress. RA also reduced citrate synthase, enzymatic mitochondrial complex II, ATP synthase, and enzymes of fatty acid metabolism and was associated with increased enzymes involved in glucose use. In addition, RA increased JNK 1/2 expression, without changes in TGF-β, PI3K, AKT, NFκB, S6K, and ERK.

Conclusion: In normal rats, RA induces cardiac hypertrophy in a dose-dependent manner. The non-participation of the PI3K/Akt pathway, associated with the participation of the JNK pathway, oxidative stress, and changes in energy metabolism, suggests that cardiac remodeling induced by RA supplementation is deleterious.
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http://dx.doi.org/10.1159/000481876DOI Listing
December 2017

An integrative analysis of chemically-induced cirrhosis-associated hepatocarcinogenesis: Histological, biochemical and molecular features.

Toxicol Lett 2017 Nov 21;281:84-94. Epub 2017 Sep 21.

Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu - SP, Brazil. Electronic address:

This study aimed the integrative characterization of morphological, biochemical and molecular features of chemically-induced cirrhosis-associated hepatocarcinogenesis. Thus, male Wistar rats were submitted to a diethylnitrosamine (DEN)/thioacetamide (TAA)-induced model. Liver tissue was processed for global gene expression, histopathological and collagen evaluations; as well as immunohistochemical and oxidative stress analysis. Gene Ontology and functional analysis showed the upregulation of extracellular matrix deposition genes, such as collagen type I alpha 1 and 2 (Col1α1 and Col1α2) and tissue inhibitor of metalloproteinase 1 and 2 genes (Timp1 and Timp2). In agreement these findings, animals presented extensive liver cirrhosis with increased collagen deposition (Sirius red). Besides, the animals developed many glutathione S-transferase pi (GST-P)-positive preneoplastic lesions showing high cell proliferation (Ki-67), in keeping with the Gstp1 and Gstp2 increased gene expression. DEN/TAA-treated rats also showed the upregulation of tumorigenesis-related annexin A2 gene (Anxa2) and few neoplastic lesions (hepatocellular adenomas, carcinomas, and cholangiocarcinoma). In contrast, gene expression and activity of antioxidant enzymes were decreased (glutathione peroxidase, total glutathione-S-transferase, and catalase). The model featured remarkable similarities to human hepatocarcinogenesis. Our findings could bring up new molecular insights into cirrhosis-associated hepatocarcinogenesis, and provide a suitable animal model for the establishment of further diagnostic, preventive and therapeutic approaches.
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http://dx.doi.org/10.1016/j.toxlet.2017.09.015DOI Listing
November 2017
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