Publications by authors named "Raquel Seiça"

116 Publications

Multiparticulate Systems of Ezetimibe Micellar System and Atorvastatin Solid Dispersion Efficacy of Low-Dose Ezetimibe/Atorvastatin on High-Fat Diet-Induced Hyperlipidemia and Hepatic Steatosis in Diabetic Rats.

Pharmaceutics 2021 Mar 20;13(3). Epub 2021 Mar 20.

Department of Pharmaceutics and Food Technology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain.

The aim of this study was to develop multiparticulate systems with a combination of ezetimibe micellar systems and atorvastatin solid dispersions using croscarmellose as a hydrophilic vehicle and Kolliphor RH40 as a surfactant. The presence of a surfactant with low hydrophilic polymer ratios produces the rapid dissolution of ezetimibe through a drug-polymer interaction that reduces its crystallinity. The solid dispersion of atorvastatin with low proportions of croscarmellose showed drug-polymer interactions sufficient to produce the fast dissolution of atorvastatin. Efficacy studies were performed in diabetic Goto-Kakizaki rats with induced hyperlipidemia. The administration of multiparticulate systems of ezetimibe and atorvastatin at low (2 and 6.7 mg/kg) and high (3 and 10 mg/kg) doses showed similar improvements in levels of cholesterol, triglycerides, lipoproteins, alanine transaminase, and aspartate transaminase compared to the high-fat diet group. Multiparticulate systems at low doses (2 and 6.7 mg/kg of ezetimibe and atorvastatin) had a similar improvement in hepatic steatosis compared to the administration of ezetimibe and atorvastatin raw materials at high doses (3 and 10 mg/kg). These results confirm the effectiveness of solid dispersions with low doses of ezetimibe and atorvastatin to reduce high lipid levels and hepatic steatosis in diabetic rats fed a high-fat diet.
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http://dx.doi.org/10.3390/pharmaceutics13030421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004026PMC
March 2021

Kinetics of radium-223 and its effects on survival, proliferation and DNA damage in lymph-node and bone metastatic prostate cancer cell lines.

Int J Radiat Biol 2021 Apr 7:1-16. Epub 2021 Apr 7.

University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Biophysics Institute of Faculty of Medicine, Coimbra, Portugal.

Background: Metastatic castration-resistant prostate cancer (mCRPC) is associated with a very unfavorable prognosis. At this advanced stage of the disease, there are several therapeutic strategies approved in recent times, being one of them Radium-223 dichloride (Radium-223). However, its mechanisms of action and the process that conducts to cell death are not fully understood. Given this, our main goal is to characterize the radiobiological effects induced by Radium-223 and to evaluate its kinetics on metastatic Prostate Cancer (mPCa) cells.

Materials And Methods: In vitro studies were conducted using two mPCa cell lines, the LNCaP and PC3, the first being derived from lymph node metastasis and the second from bone metastasis. Kinetic studies were conducted to access the capacity of these cell lines to uptake, retain and internalize the Radium-223. For the assessment of radiobiological effects, cells were first exposed to different doses of Radium-223 and the clonogenic assay was done to evaluate cell survival and to determine lethal doses (LD50). Then, the effects were also evaluated in terms of proliferation, oxidative stress, morphological changes and cell damage.

Results: Radium-223 is uptaken by mPCa cells and reaches the nucleus, where it is retained over time. Irradiation decreases cell survival and proliferation, with LNCaP cells (LD50 = 1.73mGy) being more radiosensitive than PC3 cells (LD50 = 4.20mGy). Irradiated cells showed morphological changes usually associated with apoptosis and a dose-dependent increase in DNA damage. Moreover, activation of cell cycle checkpoints occurs through ATM/CHK2 pathway, which is involved in cell cycle arrest and cell death.

Conclusions: The cytotoxic and anti-proliferative effects on both cell lines showed that Radium-223 can decrease the aggressiveness of tumor cells by decreasing the cell survival and proliferation and, also, by increasing the DNA damage. The similar results observed in both cell lines indicated that Radium-223 may have the potential to be used as a therapeutic option also for mCRPC patients with lymph node metastasis. The activation of DNA Damage Response pathways allows the possibility to understand the importance of these checkpoints as targets for new combined therapies.
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http://dx.doi.org/10.1080/09553002.2021.1906462DOI Listing
April 2021

Atherosclerotic Process in Seroreverter Children and Adolescents Exposed to Fetal Antiretroviral Therapy.

Curr HIV Res 2020 Nov 18. Epub 2020 Nov 18.

Coimbra Institute for Clinical and Biomedical Researh (iCBR) - Faculty of Medicine - University of Coimbra, Coimbra. Portugal.

Background: Human immunodeficiency virus infection is a recognized risk factor for premature atherosclerosis in children and adolescents. However, the atherosclerotic process in uninfected children exposed in utero to the virus and antiretroviral therapy is less clear.

Objective: To determine the potential cardiovascular risk associated to this in utero milieu exposition.

Material And Methods: A total of 115 individuals were studied (77 in the sample group and 38 controls). Eighteen analytical mediators involved in the atherogenic pathways (metabolic dysregulation, inflammation and prothrombotic state) were analyzed. The carotid intima-media thickness, which is a subclinical marker of atherosclerosis, was also measured.

Results: No significant statistical differences were identified between the sample and control groups, either in the biochemical or the echographic markers.

Conclusion: In utero exposure to the HIV virus and antiretroviral therapy in uninfected children and adolescents is not correlated to accelerated atherosclerosis.
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http://dx.doi.org/10.2174/1570162X18999201118155026DOI Listing
November 2020

Omentin: A novel therapeutic approach for the treatment of endothelial dysfunction in type 2 diabetes.

Free Radic Biol Med 2021 Jan 21;162:233-242. Epub 2020 Oct 21.

Institute of Physiology, ICBR, Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Background: Perivascular adipose tissue (PVAT) locally influences the functioning of blood vessels and promotes vascular complications associated with diabetes and obesity. The aim of this work was to study the impact of omentin-1 on endothelial function and PVAT in a non-obese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats with or without high fat diet.

Material And Methods: Diabetic GK rats were divided into four groups: 1) control group; 2) group treated with omentin-1; 3) group of GK rats fed a high fat diet (GKHFD) and 4) group of GKHFD treated with omentin-1. Several in vivo parameters such as adiposity and Lee indexes, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. At the vascular level, endothelial dependent and independent relaxation and contraction studies were performed in aortic rings in the absence (PVAT-) or in the presence (PVAT+) of thoracic PVAT. We also evaluated vascular oxidative stress and determined the pro-inflammatory status of PVAT.

Results: Endothelium-dependent relaxation to acetylcholine, assessed by wire myography, was impaired in GK and GKHFD rats and improved by the omentin-1 treatment. In addition, vascular superoxide production was increased in the vascular wall of diabetic rats, accompanied by reduced nitric oxide bioavailability and significantly improved by omentin treatment. PVAT anti-contractile action found under physiological conditions was lost in type 2 diabetes, and partially recovered with omentin-1 administration. In addition, omentin-1 treatment significantly improved proinflammatory and pro-oxidant PVAT phenotype (decreasing C-reactive protein and nitrotyrosine levels). Furthermore, it was observed an improvement in various systemic and metabolic biochemical parameters of diabetic animals treated for one month with omentin.

Conclusions: Omentin-1 ameliorates endothelial dysfunction in type 2 diabetes and presents therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.10.021DOI Listing
January 2021

GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes.

Pharmacol Res 2020 11 14;161:105198. Epub 2020 Sep 14.

Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (FMUC), Portugal; Instituto Politécnico de Coimbra, Coimbra Health School (ESTeSC), Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal. Electronic address:

Methylglyoxal was shown to impair adipose tissue capillarization and insulin sensitivity in obese models. We hypothesized that glyoxalase-1 (GLO-1) activity could be diminished in the adipose tissue of type 2 diabetic obese patients. Moreover, we assessed whether such activity could be increased by GLP-1-based therapies in order to improve adipose tissue capillarization and insulin sensitivity. GLO-1 activity was assessed in visceral adipose tissue of a cohort of obese patients. The role of GLP-1 in modulating GLO-1 was assessed in type 2 diabetic GK rats submitted to sleeve gastrectomy or Liraglutide treatment, in the adipose tissue angiogenesis assay and in the HUVEC cell line. Glyoxalase-1 activity was decreased in visceral adipose tissue of pre-diabetic and diabetic obese patients, together with other markers of adipose tissue dysfunction and correlated with increased HbA1c levels. Decreased adipose tissue GLO-1 levels in GK rats were increased by sleeve gastrectomy and Liraglutide, being associated with overexpression of angiogenic and vasoactive factors, as well as insulin receptor phosphorylation (Tyr1161). Moreover, GLP-1 increased adipose tissue capillarization and HUVEC proliferation in a glyoxalase-dependent manner. Lower adipose tissue GLO-1 activity was observed in dysmetabolic patients, being a target for GLP-1 in improving adipose tissue capillarization and insulin sensitivity.
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http://dx.doi.org/10.1016/j.phrs.2020.105198DOI Listing
November 2020

(Jacq.) Lodd. ex Mart. Leaves Increase SIRT1 Levels and Improve Stress Resistance.

Oxid Med Cell Longev 2020 22;2020:5238650. Epub 2020 Mar 22.

Research Group on Biotechnology and Bioprospecting Applied to Metabolism (GEBBAM), Federal University of Grande Dourados, Dourados, MS, Brazil.

Oxidative stress is a metabolic disorder linked with several chronic diseases, and this condition can be improved by natural antioxidants. The fruit pulp of the palm (Jacq.) Lodd. ex Mart. is widely used in the treatment of various illnesses, but as far as we know, there are no reports regarding the properties of its leaves. Thus, we aimed to evaluate the antioxidant activity of leaf extracts obtained with water (EA-Aa), ethanol (EE-Aa), and methanol (EM-Aa) solvents. The extracts were chemically characterized, and their antioxidant activity was assessed through the scavenging of the free radicals DPPH and ABTS. EE-Aa and EM-Aa showed the highest amounts of phenolic compounds and free radical scavenging activity. However, EA-Aa was more efficient to protect human erythrocytes against AAPH-induced hemolysis and lipid peroxidation. Thus, we further show the antioxidant effect of EA-Aa in preventing AAPH-induced protein oxidation, HO-induced DNA fragmentation, and ROS generation in Cos-7 cells. Increased levels of Sirt1, catalase, and activation of ERK and Nrf2 were observed in Cos-7 treated with EA-Aa. We also verify increased survival in nematodes , when induced to the oxidative condition by Juglone. Therefore, our results showed a typical chemical composition of plants for all extracts, but the diversity of compounds presented in EA-Aa is involved in the lower toxicity and antioxidant properties provided to the macromolecules tested, proteins, DNA, and lipids. This protective effect also proven in Cos-7 and in was probably due to the activation of the Sirt1/Nrf2 pathway. Altogether, the low toxicity and the antioxidant properties of EA-Aa showed in all the experimental models support its further use in the treatment of oxidative stress-related diseases.
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http://dx.doi.org/10.1155/2020/5238650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085880PMC
December 2020

A rat model of enhanced glycation mimics cardiac phenotypic components of human type 2 diabetes : A translational study using MRI.

J Diabetes Complications 2020 05 28;34(5):107554. Epub 2020 Feb 28.

CIBIT/ICNAS, University of Coimbra, Coimbra, Portugal; Laboratório de Bioestatística e Informática Médica, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address:

Background: The success of translational research depends on how well animal models mimic the pathophysiology of the human phenotype, and on the identification of disease mechanisms such as enhanced glycation.

Methods: Here, we studied cardiac MRI and metabolic phenotypes in human type 2 diabetes (N = 106; 55 patients+51 controls) and animal models with distinct levels of fat diet and end glycation products, to model the role of these factors in the cardiac phenotype. We included four groups of rats, designed to evaluate the role of lipid load and glucotoxicity in cardiac function and to correlate these with the cardiac phenotype observed in humans. We also aimed to assess into which extent phenotypes were related to specific risk factors.

Results: Stroke Volume (SV) and Peak Filling Rate (PFR) measures were similarly discriminative both in humans and animal models, particularly when enhanced glycation was present. Factorial analysis showed that reduction of multidimensionality into common main explanatory factors, in humans and animals, revealed components that equally explained the variance of cardiac phenotypes (87.62% and 83.75%, respectively). One of the components included, both in humans and animals, SV, PFR and peak ejection rate (PER). The other components included in both humans and animals are the following: ESV (end systolic volume), left ventricular mass (LVM) and ejection fraction (EF). These components were useful for between group discrimination.

Conclusions: We conclude that animal models of enhanced glycation and human type 2 diabetes share a striking similarity of cardiac phenotypic components and relation with metabolic changes, independently of fact content in the diet, which reinforces the role of glucose dysmetabolism in left ventricular dysfunction and provides a potentially useful approach for translational research in diabetes, in particular when testing new therapies early on during the natural history of this condition.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107554DOI Listing
May 2020

Myocardial peak systolic velocity-a tool for cardiac screening of HIV-exposed uninfected children.

Eur J Pediatr 2020 Mar 25;179(3):395-404. Epub 2019 Nov 25.

Coimbra Institute for Clinical and Biomedical Researh (iCBR) - Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

HIV-uninfected children exposed prenatally to the virus and to prophylactic antiretroviral therapy are at an uncertain risk of long-term myocardial dysfunction. This study aimed to analyse the structure and function of their ventricles and to identify potential screening tools for this at-risk population. One hundred and fifteen children (77 exposed vs 38 controls) aged between 2.7 and 16.2 years were included. An echocardiographic study was performed where both ventricles' dimensions and systolic functions were evaluated. In the left ventricle, parameters related to diastolic function were also analysed. Tissue Doppler values were determined in the basal state and after passive leg raising. Serologic analysis of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was carried out. The two groups had identical ventricular sizes and left ventricular diastolic functions. However, contractility assessed by myocardial peak systolic velocity was significantly inferior in the exposed group. These systolic echocardiographic differences were present despite similar values of NT-proBNP in both groups.Conclusion: HIV-exposed uninfected children may be vulnerable to ventricular systolic dysfunction at long term. Cardiovascular surveillance and periodic monitoring of biventricular function are therefore recommended. Myocardial peak systolic velocity may be a useful screening tool for this purpose.What is Known:• Previous studies on HIV-exposed uninfected children subjected prenatally to antiretroviral therapy have alerted to potential long-term cardiovascular toxicity effects on the left ventricle.What is New:• The study gives new insights on ventricular function and morphology in HIV-exposed uninfected children.• Myocardial peak systolic velocities are significantly inferior in this paediatric sub-group, therefore long-term cardiac surveillance is recommended.
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http://dx.doi.org/10.1007/s00431-019-03477-7DOI Listing
March 2020

Increased inflammation, oxidative stress and a reduction in antioxidant defense enzymes in perivascular adipose tissue contribute to vascular dysfunction in type 2 diabetes.

Free Radic Biol Med 2020 01 5;146:264-274. Epub 2019 Nov 5.

Institute of Physiology, iCBR, Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Background: Perivascular adipose tissue (PVAT) surrounds most large blood vessels and plays an important role in vascular homeostasis. The present study was conducted to investigate the contribution of PVAT to vascular dysfunction in a rat model of type 2 diabetes.

Material And Methods: Several in vivo parameters such as lipid profile (total cholesterol and triglyceride systemic levels), fasting glucose levels, glucose tolerance and insulin sensitivity (through glucose and insulin tolerance tests, respectively) were determined in Goto-Kakizaki (GK) diabetic rats and compared with control Wistar rats. At the vascular level, endothelial dependent and independent relaxation and contraction studies were performed in aortic rings in the absence (PVAT-) or in the presence (PVAT+) of thoracic PVAT. We also evaluated vascular oxidative stress and performed western blots, PCR and immunohistochemistry analysis of cytokines and various enzymes in PVAT.

Results: Endothelium-dependent relaxation to acetylcholine, assessed by wire myography, was impaired in GK rats and improved by the antioxidant TEMPOL and by the TLR4 inhibitor, CLI-095 suggesting an increase in oxidative stress and inflammation. In addition, vascular superoxide and peroxynitrite production was increased in the vascular wall of diabetic rats, accompanied by reduced nitric oxide bioavailability. The presence of PVAT had an anticontractile effect in response to phenylephrine in Wistar rats that was lost in GK rats. Western blot and immunohistochemistry analysis revealed that PVAT phenotype shifts, under diabetic conditions, towards a proinflammatory (with increment in CRP, CCL2, CD36), pro-oxidant (increased levels of aldose reductase, and reduced levels of antioxidant deference enzymes) and vasoconstriction state.

Conclusion: Our data suggest that this rat model of type 2 diabetes is associated with perivascular adipose dysfunction that contributes to oxidative stress, inflammation and endothelial dysfunction.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.11.002DOI Listing
January 2020

ECM-enriched alginate hydrogels for bioartificial pancreas: an ideal niche to improve insulin secretion and diabetic glucose profile.

J Appl Biomater Funct Mater 2019 Oct-Dec;17(4):2280800019848923

IBILI - Institute for Biomedical Imaging and Life Sciences, University of Coimbra, Coimbra, Portugal.

Introduction: The success of a bioartificial pancreas crucially depends on ameliorating encapsulated beta cells survival and function. By mimicking the cellular niche, the aim of this study was to develop a novel model for beta cells encapsulation capable of establishing an appropriate microenvironment that supports interactions between cells and extracellular matrix (ECM) components.

Methods: ECM components (Arg-Gly-Asp, abbreviated as RGD) were chemically incorporated in alginate hydrogels (alginate-RGD). After encapsulation, INS-1E beta cells outcome was analyzed and after their implantation in an animal model of diabetes.

Results: Our alginate-RGD model demonstrated to be a good niche for supporting beta cells viability, proliferation, and activity, namely by improving the key feature of insulin secretion. RGD peptides promoted cell-matrix interactions, enhanced endogenous ECM components expression, and favored the assembly of individual cells into multicellular spheroids, an essential configuration for proper beta cell functioning. , our pivotal model for diabetes treatment exhibited an improved glycemic profile of type 2 diabetic rats, where insulin secreted from encapsulated cells was more efficiently used.

Conclusions: We were able to successfully introduce a novel valuable function in an old ally in biomedical applications, the alginate. The proposed alginate-RGD model stands out as a promising approach to improve beta cells survival and function, increasing the success of this therapeutic strategy, which might greatly improve the quality of life of an increasing number of diabetic patients worldwide.
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http://dx.doi.org/10.1177/2280800019848923DOI Listing
May 2020

Editorial: Oxidative Stress Revisited-Major Role in Vascular Diseases.

Front Physiol 2019 21;10:788. Epub 2019 Jun 21.

Department of Biology, University of Texas at San Antonio, San Antonio, TX, United States.

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http://dx.doi.org/10.3389/fphys.2019.00788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599152PMC
June 2019

Evaluating the Impact of Different Hypercaloric Diets on Weight Gain, Insulin Resistance, Glucose Intolerance, and its Comorbidities in Rats.

Nutrients 2019 May 28;11(6). Epub 2019 May 28.

CEDOC, NOVA Medical School, Faculdade de Ciências Médicas, 1150-082 Lisboa, Portugal.

Animal experimentation has a long history in the study of metabolic syndrome-related disorders. However, no consensus exists on the best models to study these syndromes. Knowing that different diets can precipitate different metabolic disease phenotypes, herein we characterized several hypercaloric rat models of obesity and type 2 diabetes, comparing each with a genetic model, with the aim of identifying the most appropriate model of metabolic disease. The effect of hypercaloric diets (high fat (HF), high sucrose (HSu), high fat plus high sucrose (HFHSu) and high fat plus streptozotocin (HF+STZ) during different exposure times (HF 3 weeks, HF 19 weeks, HSu 4 weeks, HSu 16 weeks, HFHSu 25 weeks, HF3 weeks + STZ) were compared with the Zucker fatty rat. Each model was evaluated for weight gain, fat mass, fasting plasma glucose, insulin and C-peptide, insulin sensitivity, glucose tolerance, lipid profile and liver lipid deposition, blood pressure, and autonomic nervous system function. All animal models presented with insulin resistance and dyslipidemia except the HF+STZ and HSu 4 weeks, which argues against the use of these models as metabolic syndrome models. Of the remaining animal models, a higher weight gain was exhibited by the Zucker fatty rat and wild type rats submitted to a HF diet for 19 weeks. We conclude that the latter model presents a phenotype most consistent with that observed in humans with metabolic disease, exhibiting the majority of the phenotypic features and comorbidities associated with type 2 diabetes in humans.
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http://dx.doi.org/10.3390/nu11061197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627141PMC
May 2019

Effect of Sleeve Gastrectomy on Angiogenesis and Adipose Tissue Health in an Obese Animal Model of Type 2 Diabetes.

Obes Surg 2019 09;29(9):2942-2951

Institute of Physiology and Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Polo III, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.

Introduction: Metabolic surgery has become an accepted option for the treatment of obesity and associated metabolic diseases like hypertension and type 2 diabetes. Adipose tissue dysfunction and ectopic storage of excess lipids are thought to be involved in the underlying pathophysiological process.

Objectives: The present study aims to clarify the effect of sleeve gastrectomy (SG) on adipose tissue microvasculature and health in an animal model of adipose type 2 diabetes.

Methods: After weaning, diabetic Goto-Kakizaki rats were either fed on standard rat chow or high-calorie diet. At 4 months, animals on high-calorie diet were randomized to SG, sham surgery, or control group. Non-diabetic Wistar rats served as further controls. At 6 months, glucose and lipid metabolisms were studied in vivo. After sacrifice, periepididymal adipose tissue was collected for histology and analysis of parameters of adipose tissue metabolism and insulin sensitivity.

Results: SG decreased body and adipose tissue weight and improved glycemic and lipid profiles. Fasting glycemia, area under the curve after intraperitoneal insulin tolerance test, and insulin resistance were decreased in operated animals. SG also reduced circulating triglycerides and cholesterol while increasing serum adiponectin and adipose tissue peroxisome proliferator-activated receptor γ (PPAR-γ) and perilipin A. Additionally, surgery improved adipose tissue vascular function and markedly increased vascular endothelial growth factor, cluster of differentiation 31, and endothelial nitric oxide synthase.

Conclusions: In our obese animal model of type 2 diabetes, SG significantly improved adipose tissue health and angiogenesis while reducing insulin resistance, involving PPAR-γ and markers of sprouting angiogenesis and endothelial function.
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http://dx.doi.org/10.1007/s11695-019-03935-zDOI Listing
September 2019

Association between Adipokines and Biomarkers of Alzheimer's Disease: A Cross-Sectional Study.

J Alzheimers Dis 2019 ;67(2):725-735

Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.

Background: Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer's disease. However, the involvement of adipokines, particularly adiponectin, remains unclear.

Objective: To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer's disease and evaluate their relationship with classical biomarkers and their value as markers of progression.

Methods: Amnestic mild cognitive impairment (MCI, n = 71) and Alzheimer's dementia (AD, n = 53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman's correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines.

Results: Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95% CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85μg/ml maximized the sum of specificity (87%) and sensitivity (44%).

Conclusion: Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer's disease.
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http://dx.doi.org/10.3233/JAD-180669DOI Listing
March 2020

Subcutaneous delivery of biotherapeutics: challenges at the injection site.

Expert Opin Drug Deliv 2019 02 24;16(2):143-151. Epub 2019 Jan 24.

a Department of Pharmaceutical Technology, Faculty of Pharmacy , University of Coimbra , Coimbra , Portugal.

Introduction: Biotherapeutics are primarily delivered subcutaneously due to better compliance and prolonged rate of absorption compared to other parenteral administration routes. Recent research has allowed for the development of biotherapeutic formulations for subcutaneous delivery that require a lower frequency of administration by increasing drug half-life. Formulations determine shelf-life stability as well as features and transient behaviors that influence stability once implanted in the subcutaneous space.

Areas Covered: This review provides an overview of the factors affecting subcutaneous absorption with a focus on transient effects at the injection site following administration of biotherapeutics and the subsequent impact on absorption and stability.

Expert Opinion: Advances have been made in understanding subcutaneous tissue and the complex interplay of factors that regulate its homeostasis. The issue of poor stability after injection has been neglected, and many biotherapeutics are hampered by low bioavailability. With the advent of new in vitro techniques that account for properties of the injection site, stability studies evaluating subcutaneous tissues and impacts on pharmacokinetics of biotherapeutics may be useful in the development of new formulations.
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http://dx.doi.org/10.1080/17425247.2019.1568408DOI Listing
February 2019

Vascular Oxidative Stress: Impact and Therapeutic Approaches.

Front Physiol 2018 4;9:1668. Epub 2018 Dec 4.

College of Sciences, One UTSA Circle, University of Texas at San Antonio, San Antonio, TX, United States.

Oxidative stress has been defined as an imbalance between oxidants and antioxidants and more recently as a disruption of redox signaling and control. It is generally accepted that oxidative stress can lead to cell and tissue injury having a fundamental role in vascular dysfunction. Physiologically, reactive oxygen species (ROS) control vascular function by modulating various redox-sensitive signaling pathways. In vascular disorders, oxidative stress instigates endothelial dysfunction and inflammation, affecting several cells in the vascular wall. Vascular ROS are derived from multiple sources herein discussed, which are prime targets for therapeutic development. This review focuses on oxidative stress in vascular physiopathology and highlights different strategies to inhibit ROS production.
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http://dx.doi.org/10.3389/fphys.2018.01668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288353PMC
December 2018

Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation.

Int J Mol Sci 2018 Sep 11;19(9). Epub 2018 Sep 11.

Institute of Physiology, Faculty of Medicine, University of Coimbra; Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal.

Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.
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http://dx.doi.org/10.3390/ijms19092706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164246PMC
September 2018

Subcutaneous delivery of monoclonal antibodies: How do we get there?

J Control Release 2018 09 2;286:301-314. Epub 2018 Aug 2.

Faculty of Pharmacy, University of Coimbra, Portugal; I3S - Institute for Research and Innovation in Health, University of Porto, Portugal. Electronic address:

The convenience of subcutaneous (SC) administration and the increasing interest in monoclonal antibody (mAb)-based therapies for chronic diseases, hint their potential for SC delivery in a near future. In addition, there is a common interest among patients, clinicians and pharmaceutical industry in moving from intravenous to SC administration of mAbs due to benefits of improved patient compliance and reduced costs to the healthcare system. Despite the wide use of this route of administration in diseases like diabetes and rheumatoid arthritis, SC bioavailability of mAbs has been shown to be incomplete and variable in most preclinical and clinical studies. This evidences a gap in the understanding of SC absorption process of mAbs and in their drug development process. Likewise, challenges present in drug formulation, such as high viscosity and aggregation, and the inherent immunogenicity of mAbs have also been hampering the successful translation to clinical settings. This review provides a characterization of the subcutaneously delivered mAbs that have entered the market in the last 10 years as well as a snapshot of the landscape of currently undergoing clinical trials. Moreover, there is an overview of the factors influencing SC absorption of mAbs and the preclinical models in use to study SC pharmacokinetics. Considerations about drug formulation and immunogenicity of mAbs are also explored.
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http://dx.doi.org/10.1016/j.jconrel.2018.08.001DOI Listing
September 2018

Tissular growth factors profile after teduglutide administration on an animal model of intestinal anastomosis.

Nutr Hosp 2018 Jan 16;35(1):185-193. Epub 2018 Jan 16.

"A" Surgical Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Background: Teduglutide is an enterotrophic analogue of glucagon-like peptide-2, with an indirect and poorly understood mechanism of action, approved for the rehabilitation of short-bowel syndrome. This study aims to analyze the response of tissue growth factors to surgical injury and teduglutide administration on an animal model of intestinal anastomosis.

Methods: Wistar rats (n = 59) were distributed into four groups: "ileal resection" or "laparotomy", each one subdivided into "postoperative teduglutide administration" or "no treatment"; and sacrificed at the third or the seventh day, with ileal sample harvesting. Gene expression of insulin-like growth factor 1 (Igf1), vascular endothelial growth factor a (Vegfa), transforming growth factor β1 (Tgfβ1), connective tissue growth factor (Ctgf), fibroblast growth factor 2 (Fgf2), fibroblast growth factor 7 (Fgf7), epidermal growth factor (Egf), heparin-binding epidermal-like growth factor (Hbegf), platelet-derived growth factor b (Pdgfb) and glucagon-like peptide 2 receptor (Glp2r)was studied by real-time polymerase chain reaction.

Results: Upregulation of Fgf7, Fgf2, Egf, Vegfaand Glp2rat the third day and of Pdgfat the seventh day was verified in the perianastomotic segment. Teduglutide administration was associated with higher fold-change of relative gene expression of Vegfa(3.6 ± 1.3 vs.1.9 ± 2.0, p = 0.0001), Hbegf(2.2 ± 2.3 vs. 1.1 ± 0.9, p = 0.001), Igf1(1.6 ± 7.6 vs. 0.9 ± 0.7, p = 0.002) and Ctgf(1.1 ± 2.1 vs. 0.6 ± 2.0, p = 0.013); and lower fold-change of Tgfβ1, Fgf7and Glp2r.

Conclusions: Those results underscore the recognized role of Igf1and Hbegfas molecular mediators of the effects of teduglutide and suggest that other humoral factors, like Vegfand Ctgf, may also be relevant in the perioperative context. Induction of Vegfa, Igf1and Ctgfgene expressions might indicate a favorable influence of teduglutide on the intestinal anastomotic healing.
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http://dx.doi.org/10.20960/nh.1326DOI Listing
January 2018

High-fat diet induces a neurometabolic state characterized by changes in glutamate and N-acetylaspartate pools associated with early glucose intolerance: An in vivo multimodal MRI study.

J Magn Reson Imaging 2018 Jan 26. Epub 2018 Jan 26.

Center for Neuroscience and Cell Biology - Institute of Biomedical Imaging and Life Science (CNC.IBILI), University of Coimbra, Coimbra, Portugal.

Background: Type-2 diabetes mellitus (T2DM) is a metabolic disorder with a broad range of complications in the brain that depend on the conditions that precede its onset, such as obesity and metabolic syndromes. It has been suggested that neurotransmitter and metabolic perturbations may emerge even before the early stages of T2DM and that high-caloric intake could adversely influence the brain in such states. Notwithstanding, evidence for neurochemical and structural alterations in these conditions are still sparse and controversial.

Purpose: To evaluate the influence of high-fat diet in the neurochemical profile and structural integrity of the rodent brain.

Study Type: Prospective.

Subjects: Wistar rats (n = 12/group).

Field Strength/sequence: A PRESS, ISIS, RARE, and EPI sequences were performed at 9.4T.

Assessment: Neurochemical and structural parameters were assessed by magnetic resonance spectroscopy, voxel-based morphometry, volumetry, and diffusion tensor imaging.

Statistical Tests: Measurements were compared through Student and Mann-Whitney tests. Pearson correlation was used to assess relationships between parameters.

Results: Animals submitted to high-caloric intake gained weight (P = 0.003) and developed glucose intolerance (P < 0.001) but not hyperglycemia. In the hippocampus, the diet induced perturbations in glutamatergic metabolites reflected by increased levels of glutamine (P = 0.016) and glutamatergic pool (Glx) (P = 0.036), which were negatively correlated with glucose intolerance (glutamine, r = -0.804, P = 0.029), suggesting a link with neurometabolic dysregulation. At caudate-putamen, high-fat diet led to a surprising increase in the pool of N-acetylaspartate (P = 0.028). A relation with metabolic changes was again suggested by the negative correlation between glucose intolerance and levels of glutamatergic metabolites in this region (glutamate, r = -0.845, P = 0.014; Glx, r = -0.834, P = 0.020). Neither changes in phosphate compounds nor major structural alterations were observed for both regions.

Data Conclusion: We found evidence that high-fat diet-induced obesity leads to distinct early and region-specific metabolic/neurochemical imbalances in the presence of early glucose intolerance even when structural alterations or T2DM are absent.

Level Of Evidence: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.
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http://dx.doi.org/10.1002/jmri.25942DOI Listing
January 2018

Using Resistin, glucose, age and BMI to predict the presence of breast cancer.

BMC Cancer 2018 01 4;18(1):29. Epub 2018 Jan 4.

Laboratory of Biostatistics and Medical Informatics and IBILI - Faculty of Medicine, University of Coimbra, Azinhaga Santa Comba, Celas, 3000-548, Coimbra, Portugal.

Background: The goal of this exploratory study was to develop and assess a prediction model which can potentially be used as a biomarker of breast cancer, based on anthropometric data and parameters which can be gathered in routine blood analysis.

Methods: For each of the 166 participants several clinical features were observed or measured, including age, BMI, Glucose, Insulin, HOMA, Leptin, Adiponectin, Resistin and MCP-1. Machine learning algorithms (logistic regression, random forests, support vector machines) were implemented taking in as predictors different numbers of variables. The resulting models were assessed with a Monte Carlo Cross-Validation approach to determine 95% confidence intervals for the sensitivity, specificity and AUC of the models.

Results: Support vector machines models using Glucose, Resistin, Age and BMI as predictors allowed predicting the presence of breast cancer in women with sensitivity ranging between 82 and 88% and specificity ranging between 85 and 90%. The 95% confidence interval for the AUC was [0.87, 0.91].

Conclusions: These findings provide promising evidence that models combining age, BMI and metabolic parameters may be a powerful tool for a cheap and effective biomarker of breast cancer.
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http://dx.doi.org/10.1186/s12885-017-3877-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755302PMC
January 2018

[Premature Atherosclerosis in HIV-Infected Pediatric Patients: Literature Review and Clinical Approach].

Acta Med Port 2017 Oct 31;30(10):742-749. Epub 2017 Oct 31.

Laboratório de Fisiologia. Instituto de Imagem Biomédica e Ciências da Vida (IBILI). Faculdade de Medicina. Universidade de Coimbra. Coimbra. Portugal.

Human immunodeficiency virus infected children and adolescents are a pediatric group with increased risk of premature cardiovascular disease. The virus itself, the antiretroviral therapy and the lifestyle establish a complex interplay of factors that promotes an accelerated atherosclerosis. This process is probably mediated by dyslipidaemia, dysregulation of glucose metabolism, lipodystrophy, inflammation, endothelial dysfunction and a prothrombotic state. The clinical approach to this population in terms of cardiovascular prevention is mainly based on efficient treatment of the infection, reduction of the modifiable risk factors and promotion of lifestyle changes.
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http://dx.doi.org/10.20344/amp.8726DOI Listing
October 2017

The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes.

Sci Rep 2017 10 30;7(1):14357. Epub 2017 Oct 30.

Physiology, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions to determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products (AGE) formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes, were treated with or without PM and/or SFN during 8 weeks and compared with age-matched Wistar rats. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability and vascular oxidative stress, AGE and Nrf2 levels were also assessed. Diabetic GK rats presented significantly lower levels of Nrf2 and concomitantly exhibited higher levels of oxidative stress and endothelial dysfunction. PM and SFN as monotherapy were capable of significantly improving endothelial dysfunction in aorta and mesenteric arteries decreasing vascular oxidative damage, AGE and HbA1c levels. Furthermore, SFN + PM proved more effective reducing systemic free fatty acids levels, normalizing endothelial function, NO bioavailability and glycation in GK rats. Activators of Nrf2 can be used therapeutically in association with inhibitors of AGE and cross-linking formation to normalize endothelial dysfunction in type 2 diabetes.
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http://dx.doi.org/10.1038/s41598-017-14733-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662716PMC
October 2017

Adiponectin and sporadic Alzheimer's disease: Clinical and molecular links.

Front Neuroendocrinol 2019 01 13;52:1-11. Epub 2017 Oct 13.

Institute of Physiology, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Electronic address:

Obesity has been consistently associated with Alzheimer's disease (AD) though the exact mechanisms by which it influences cognition are still elusive and subject of current research. Adiponectin, the most abundant adipokine in circulation, is inversely correlated with adipose tissue dysfunction and seems to be a central player in this association. In fact, different signalling pathways are shared by adiponectin and proteins involved in AD pathophysiology and considerable amount of evidence supports its direct and indirect influence on β-amyloid and tau aggregates formation. In this paper we present a critical review of cellular, animal and clinical studies which have contributed to a more thorough understanding of the extent to which adiponectin influences the risk of developing AD as well as its progression. Finally, the effect of acetylcholinesterase inhibitors on circulating adiponectin levels, possible therapeutic applications and future research strategies are also discussed.
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http://dx.doi.org/10.1016/j.yfrne.2017.10.002DOI Listing
January 2019

Diabesity and Brain Energy Metabolism: The Case of Alzheimer's Disease.

Adv Neurobiol 2017 ;19:117-150

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

It is widely accepted that high calorie diets and a sedentary lifestyle sturdily influence the incidence and outcome of type 2 diabetes and obesity, which can occur simultaneously, a situation called diabesity. Tightly linked with metabolic and energy regulation, a close association between diabetes and Alzheimer's disease (AD) has been proposed. Among the common pathogenic mechanisms that underpin both conditions, insulin resistance, brain glucose hypometabolism, and metabolic dyshomeostasis appear to have a pivotal role. This century is an unprecedented diabetogenic period in human history, so therapeutic strategies and/or approaches to control and/or revert this evolving epidemic is of utmost importance. This chapter will make a brief contextualization about the impact that diabetes and obesity can exert in brain structure and function alongside with a brief survey about the role of insulin in normal brain function, exploring its roles in cognition and brain glucose metabolism. Later, attention will be given to the intricate relation of diabesity, insulin resistance, and AD. Finally, both pharmacological and lifestyle interventions will also be reviewed as strategies aimed at fighting diabesity and/or AD-related metabolic effects.
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http://dx.doi.org/10.1007/978-3-319-63260-5_5DOI Listing
November 2018

Neuroendocrinology of Adipose Tissue and Gut-Brain Axis.

Adv Neurobiol 2017 ;19:49-70

Institute of Physiology, Institute for Biomedical Imaging and Life Sciences-IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Food intake and energy expenditure are closely regulated by several mechanisms which involve peripheral organs and nervous system, in order to maintain energy homeostasis.Short-term and long-term signals express the size and composition of ingested nutrients and the amount of body fat, respectively. Ingested nutrients trigger mechanical forces and gastrointestinal peptide secretion which provide signals to the brain through neuronal and endocrine pathways. Pancreatic hormones also play a role in energy balance exerting a short-acting control regulating the start, end, and composition of a meal. In addition, insulin and leptin derived from adipose tissue are involved in long-acting adiposity signals and regulate body weigh as well as the amount of energy stored as fat over time.This chapter focuses on the gastrointestinal-, pancreatic-, and adipose tissue-derived signals which are integrated in selective orexigenic and anorexigenic brain areas that, in turn, regulate food intake, energy expenditure, and peripheral metabolism.
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http://dx.doi.org/10.1007/978-3-319-63260-5_3DOI Listing
November 2018

The Role of Brain in Energy Balance.

Adv Neurobiol 2017 ;19:33-48

Institute of Physiology, Institute for Biomedical Imaging and Life Sciences-IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Energy homeostasis is regulated by homeostatic and nonhomeostatic reward circuits which are closely integrated and interrelated. Before, during, and after meals, peripheral nutritional signals, through hormonal and neuronal pathways, are conveyed to selective brain areas, namely the hypothalamic nuclei and the brainstem, the main brain areas for energy balance regulation. These orexigenic and anorexigenic centers are held responsible for the integration of those signals and for an adequate output to peripheral organs involved in metabolism and energy homeostasis.Feeding includes also a hedonic behavior defined as food intake for pleasure independently of energy requirement. This nonhomeostatic regulation of energy balance is based on food reward properties, unrelated to nutritional demands, and involves areas like mesolimbic reward system, such as the ventral tegmental area and the nucleus accumbens, and also opioid, endocannabinoid, and dopamine systems.Herein, focus will be put on the brain circuits of homeostatic and nonhomeostatic regulation of food intake and energy expenditure.
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http://dx.doi.org/10.1007/978-3-319-63260-5_2DOI Listing
November 2018

Function and Dysfunction of Adipose Tissue.

Adv Neurobiol 2017 ;19:3-31

Institute of Physiology, Institute for Biomedical Imaging and Life Sciences-IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Adipose tissue is an endocrine organ which is responsible for postprandial uptake of glucose and fatty acids, consequently producing a broad range of adipokines controlling several physiological functions like appetite, insulin sensitivity and secretion, immunity, coagulation, and vascular tone, among others. Many aspects of adipose tissue pathophysiology in metabolic diseases have been described in the last years. Recent data suggest two main factors for adipose tissue dysfunction: accumulation of nonesterified fatty acids and their secondary products and hypoxia. Both of these factors are thought to be on the basis of low-grade inflammatory activation, further increasing metabolic dysregulation in adipose tissue. In turn, inflammation is involved in the inhibition of substrate uptake, alteration of the secretory profile, stimulation of angiogenesis, and recruitment of further inflammatory cells, which creates an inflammatory feedback in the tissue and is responsible for long-term establishment of insulin resistance.
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http://dx.doi.org/10.1007/978-3-319-63260-5_1DOI Listing
November 2018

Intestinal inflammatory and redox responses to the perioperative administration of teduglutide in rats.

Acta Cir Bras 2017 Aug;32(8):648-661

PhD, Department of Surgery "A", Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Portugal. Critical revision.

Purpose: : To investigate the inflammatory and redox responses to teduglutide on an animal model of laparotomy and intestinal anastomosis.

Methods:: Wistar rats (n=62) were allocated into four groups: "Ileal Resection and Anastomosis" vs. "Laparotomy", each one split into "Postoperative Teduglutide Administration" vs. "No Treatment"; and euthanized at the third or the seventh day. Ileal and blood samples were recovered at the baseline and at the euthanasia. Flow cytometry was used to study the inflammatory response (IL-1α, MCP-1, TNF-α, IFN-γ and IL-4 levels), oxidative stress (cytosolic peroxides, mitochondrial reactive species, intracellular glutathione and mitochondrial membrane potential) and cellular viability and death (annexin V/propidium iodide double staining).

Results:: Postoperative teduglutide treatment was associated with higher cellular viability index and lower early apoptosis ratio at the seventh day; higher cytosolic peroxides level at the third day and mitochondrial overgeneration of reactive species at the seventh day; higher tissue concentration of IL-4 and lower local pro-to-anti-inflammatory cytokines ratio at the seventh day.

Conclusion: : Those findings suggest an intestinal pro-oxidative and anti-inflammatory influence of teduglutide on the peri-operative context with a potential interference in the intestinal anastomotic healing.
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http://dx.doi.org/10.1590/s0102-865020170080000007DOI Listing
August 2017

Uncoupling Protein 2 Inhibition Exacerbates Glucose Fluctuation-Mediated Neuronal Effects.

Neurotox Res 2018 02 5;33(2):388-401. Epub 2017 Sep 5.

Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504, Coimbra, Portugal.

Though glucose fluctuations have been considered as an adverse factor for the development of several diabetes-related complications, their impact in the central nervous system is still not fully elucidated. This study was conducted to evaluate the responses of neuronal cells to different glycemic exposures alongside to elucidate the role of uncoupling protein 2 (UCP2) in regulating such responses. To achieve our goals, primary cortical neurons were submitted to constant high (HG)/low (LG) or glucose level variations (GVs), and the pharmacological inhibition of UCP2 activity was performed using genipin. Results obtained show that GV decreased neuronal cells' viability, mitochondrial membrane potential, and manganese superoxide dismutase activity and increased reactive oxygen species (ROS) production. GV also caused an increase in the glutathione/glutathione disulfide ratio and in the protein expression levels of nuclear factor E2-related factor 2 (NRF2), UCP2, NADH-ubiquinone oxidoreductase chain 1 (ND1), and mitochondrially encoded cytochrome c oxidase I (MTCO1), both mitochondrial DNA encoded subunits of the electron transport chain. Contrariwise, genipin abrogated all those compensations and increased the levels of caspase 3-like activity, potentiated mitochondrial ROS levels, and the loss of neuronal synaptic integrity, decreased the protein expression levels of NRF1, and increased the protein expression levels of UCP5. Further, in the control and LG conditions, genipin increased mitochondrial ROS and the protein expression levels of UCP4, postsynaptic density protein 95 (PSD95), ND1, and MTCO1. Overall, these observations suggest that UCP2 is in the core of neuronal cell protection and/or adaptation against GV-mediated effects and that other isoforms of neuronal UCPs can be upregulated to compensate the inhibition of UCP2 activity.
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http://dx.doi.org/10.1007/s12640-017-9805-yDOI Listing
February 2018