Publications by authors named "Sara Nunes"

82 Publications

18F-FDG PET/CT in Patients with Vulvar and Vaginal Cancer: A Preliminary Study of 20 Cases.

Acta Med Port 2021 Nov 24. Epub 2021 Nov 24.

Serviço de Medicina Nuclear. Centro Hospitalar de São João. Porto. Portugal.

Introduction: Despite the growing evidence supporting the use of 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography in cervical and ovarian malignant tumours, data on vulvar and vaginal cancer is sparse. Our aim was to assess the role of 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography in patients with vulvar and vaginal cancer.

Material And Methods: A retrospective study was conducted on a cohort of 20 patients with biopsy-proven vulvar (n = 17) and vaginal (n = 3) cancer who performed 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography, between January 2013 and April 2018. We collected the clinical data of all patients, as well as the indication for 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography, its results, and the main lesion maximum standard uptake value (SUVmax). In addition, we correlated the results of 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography with other diagnostic modalities, namely histological findings, computed tomography and magnetic resonance imaging. Patients were divided into two groups, one with newly diagnosed disease and another with recurrent disease.

Results: Six patients had newly diagnosed disease and 14 had recurrent disease. The main lesion was detected by 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography in five out of six patients with newly diagnosed disease and in all 14 patients with recurrent disease. Additional sites of 2-[F-18]-fluor-2-desoxi-D-glucose uptake were identified in inguinal and iliac lymph nodes and in distant lesions. Magnetic resonance imaging and computed tomography were performed in 12 cases. In four patients with recurrent disease, abnormalities (main lesion/ metastatic lymph nodes) identified by 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography were not detected as suspicious by computed tomography.

Discussion: In our study, 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography identified abnormalities more often than conventional computed tomography scans in recurrent disease. In comparison with histology, 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography had a sensitivity of 95% and a positive predictive value of 100% in identifying the primary tumour and the recurrent main lesion. Little data is available regarding the usefulness of 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography in the management of vulvar and vaginal cancers. The existing evidence supports a high accuracy in detecting lymph node metastases and a change of 36.0% - 61.5% in patient management. Our findings reinforce the usefulness of this technique in vulvar and vaginal cancer. Limitations of our study include its retrospective nature and the rareness of both vulvar and vaginal cancer, which leads to a small sample size and few comparative imaging tests.

Conclusion: In this preliminary study, 2-[F-18]-fluor-2-desoxi-D-glucose positron emission tomography/computed tomography demonstrated it can be a useful method in patients with vulvar and vaginal cancers, namely in defining the extent of disease and contributing to accurate staging and restaging.
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http://dx.doi.org/10.20344/amp.12510DOI Listing
November 2021

DC-SIGN Mediates the Interaction Between Neutrophils and -Infected Dendritic Cells to Promote DC Maturation and Parasite Elimination.

Front Immunol 2021 1;12:750648. Epub 2021 Nov 1.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.

Background: Leishmaniasis is a neglected arthropod-borne disease that affects millions of people worldwide. Successful infections require the mitigation of immune cell functions leading to parasite survival and proliferation. A large body of evidence highlights the involvement of neutrophils (PMNs) and dendritic cells (DCs) in the establishment of immunological responses against these parasites. However, few studies, contemplate to what extent these cells interact synergistically to constrain infection.

Objective: We sought to investigate how PMNs and infected DCs interact in an model of infection.

Material And Methods: Briefly, human PMNs and DCs were purified from the peripheral blood of healthy donors. Next, PMNs were activated with fibronectin and subsequently co-cultured with -infected DCs.

Results: We observed that -infected DC exhibited lower rates of infection when co-cultivated with either resting or activated PMNs. Surprisingly, we found that the release of neutrophil enzymes was not involved in killing. Next, we showed that the interaction between PMNs and infected-DCs was intermediated by DC-SIGN, further suggesting that parasite elimination occurs in a contact-dependent manner. Furthermore, we also observed that TNFα and ROS production was dependent on DC-SIGN-mediated contact, as well as parasite elimination is dependent on TNFα production in the co-culture. Finally, we observed that direct contact between PMNs and DCs are required to restore the expression of DC maturation molecules during infection.

Conclusion: Our findings suggest that the engagement of direct contact between PMNs and -infected DC DC-SIGN is required for the production of inflammatory mediators with subsequent parasite elimination and DC maturation.
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http://dx.doi.org/10.3389/fimmu.2021.750648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591281PMC
November 2021

Cell-based therapies for vascular regeneration: Past, present and future.

Pharmacol Ther 2021 Sep 1:107976. Epub 2021 Sep 1.

Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3H2, Canada. Electronic address:

Tissue vascularization remains one of the outstanding challenges in regenerative medicine. Beyond its role in circulating oxygen and nutrients, the vasculature is critical for organ development, function and homeostasis. Importantly, effective vascular regeneration is key in generating large 3D tissues for regenerative medicine applications to enable the survival of cells post-transplantation, organ growth, and integration into the host system. Therefore, the absence of clinically applicable means of (re)generating vessels is one of the main obstacles in cell replacement therapy. In this review, we highlight cell-based vascularization strategies which demonstrate clinical potential, discuss their strengths and limitations and highlight the main obstacles hindering cell-based therapeutic vascularization.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107976DOI Listing
September 2021

Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models.

Cell Stem Cell 2021 11 3;28(11):1936-1949.e8. Epub 2021 Sep 3.

McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Islet transplantation is a promising treatment for type 1 diabetes (T1D), yet the low donor pool, poor islet engraftment, and life-long immunosuppression prevent it from becoming the standard of care. Human embryonic stem cell (hESC)-derived pancreatic cells could eliminate donor shortages, but interventions to improve graft survival are needed. Here, we enhanced subcutaneous engraftment by employing a unique vascularization strategy based on ready-made microvessels (MVs) isolated from the adipose tissue. This resulted in improved cell survival and effective glucose response of both human islets and hESC-derived pancreatic cells, which ameliorated preexisting diabetes in three mouse models of T1D.
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http://dx.doi.org/10.1016/j.stem.2021.08.001DOI Listing
November 2021

Blueberry as an Attractive Functional Fruit to Prevent (Pre)Diabetes Progression.

Antioxidants (Basel) 2021 Jul 22;10(8). Epub 2021 Jul 22.

Institute of Pharmacology & Experimental Therapeutics & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

Prediabetes, a subclinical impairment between euglycemia and hyperglycemia, is a risk factor for the development of type 2 diabetes mellitus (T2DM) and associated micro- and macrovascular complications. Lifestyle therapy, the first-line treatment of prediabetes, includes physical exercise and dietary regimens enriched in phytochemicals with health-related properties. Blueberries ( spp.), given their pleasant taste and great abundance in beneficial phytochemicals, have gained public interest all over the world. Along with a high antioxidant activity, this functional fruit is also well-recognized due to its hypoglycemic and insulin-sensitizing effects and has been recommended for overt T2DM management. Yet blueberries target several other pathophysiological traits, namely gut microbiota dysbiosis and hepatic dysmetabolism, that ensue when prediabetes begins and for which pharmacological interventions tend to be delayed. In this work, we revisited preclinical data from in vitro assays, animal models and human studies, aiming to disclose the potential mechanisms by which blueberries may be a fruitful source of phytochemicals able to prevent (pre)diabetes progression. Collectively, future efforts should focus on longer-term studies with standardized interventions and readouts, particularly in humans, that will hopefully bring more robust evidence and concrete guidance for blueberries' effective use in prediabetes.
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http://dx.doi.org/10.3390/antiox10081162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389043PMC
July 2021

Obtainment of Macrophages from Human Monocytes to Assess Leishmania braziliensis Infection Rate and Innate Host Immune Response.

J Vis Exp 2021 08 7(174). Epub 2021 Aug 7.

Oswaldo Cruz Foundation, Gonçalo Moniz Institute; Federal University of Bahia;

Macrophages are multifunctional cells essential to the immune system function, and the primary host cell in Leishmania braziliensis (Lb) infection. These cells are specialized in microorganism recognition and phagocytosis, but also activate other immune cells and present antigens, as well as promote inflammation and tissue repair. Here, we describe a protocol to obtain mononuclear cells from peripheral blood (PBMC) of healthy donors to separate monocytes that then differentiate into macrophages. These cells can then be infected in vitro at different Lb concentrations to evaluate the ability to control infection, as well as evaluate host cell immune response, which can be measured by several methods. PBMCs were first isolated by centrifuging with Ficoll-Hypaque gradient and then plated to allow monocytes to adhere to culture plates; non-adherent cells were removed by washing. Next, adherent cells were cultured with macrophage-colony stimulating factor (M-CSF) for 7 days to induce macrophage differentiation. We suggest plating 2 x 10 cells per well on 24-well plates in order to obtain 2 x 10 macrophages. Fully differentiated macrophages can then be infected with Lb for 4 or 24 hours. This protocol results in a significant percentage of infected cells, which can be assessed by optical or fluorescence microscopy. In addition to infection index, parasite load can be measured by counting the numbers of parasites inside each cell. Further molecular and functional assays can also be performed in culture supernatants or within the macrophages themselves, which allows this protocol to be applied in a variety of contexts and also adapted to other intracellular parasite species.
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http://dx.doi.org/10.3791/62555DOI Listing
August 2021

LTB-Driven Inflammation and Increased Expression of / During Severe COVID-19 in Individuals With Diabetes.

Diabetes 2021 09 15;70(9):2120-2130. Epub 2021 Jun 15.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil

Diabetes is a known risk factor for severe coronavirus disease 2019 (COVID-19), the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is a lack of knowledge about the mechanisms involved in the evolution of COVID-19 in individuals with diabetes. We aimed to evaluate whether the chronic low-grade inflammation of diabetes could play a role in the development of severe COVID-19. We collected clinical data and blood samples of patients with and without diabetes hospitalized for COVID-19. Plasma samples were used to measure inflammatory mediators and peripheral blood mononuclear cells, for gene expression analysis of the SARS-CoV-2 main receptor system (/), and for the main molecule of the leukotriene B (LTB) pathway (). We found that diabetes activates the LTB pathway and that during COVID-19 it increases / as well as expression. Diabetes was also associated with COVID-19-related disorders, such as reduced oxygen saturation as measured by pulse oximetry/fraction of inspired oxygen (FiO) and arterial partial pressure of oxygen/FiO levels, and increased disease duration. In addition, the expressions of and are positively correlated, with increased expression in patients with diabetes and COVID-19 requiring intensive care assistance. We confirmed these molecular results at the protein level, where plasma LTB is significantly increased in individuals with diabetes. In addition, IL-6 serum levels are increased only in individuals with diabetes requiring intensive care assistance. Together, these results indicate that LTB and IL-6 systemic levels, as well as / blood expression, could be early markers of severe COVID-19 in individuals with diabetes.
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http://dx.doi.org/10.2337/db20-1260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576416PMC
September 2021

Repeated Positive Cervical HPV Testing and Absent or Minor Cytology Abnormality at Pap Smear. What is the Next Step?

Asian Pac J Cancer Prev 2021 Jun 1;22(6):1907-1912. Epub 2021 Jun 1.

Health Sciences Research Centre (CICS), Faculty of Health Sciences, University of Beira Interior (UBI), Covilhã, Portugal.

Background: Human papillomavirus (HPV) screening has significantly reduced cervical cancer (CC) mortality. Women who consecutively test positive for high-risk HPV without and minor changes on reflex cytology (atypical squamous cells of undetermined significance [ASC-US] or low-grade squamous intraepithelial lesion [LSIL]) or dysplasia on cervical colposcopy-oriented biopsy are always referred to colposcopy. The aim of the present study was to assess whether this guidance is appropriate for COBAS HPV testing with reflex cytology.

Methods: A cross-sectional, retrospective study was carried out in 5,227 women who underwent routine CC screening over a period of five years (2012-2017). All HPV tests were performed using Cobas®4800 HPV. The study included women attending gynecology appointments whose first HPV test was positive and who had any type of follow-up. Patients' HPV test results as well as cytology and biopsy findings obtained during the abovementioned period were analyzed. A descriptive and comparative statistical study was conducted using this data.

Results: A total of 765 out of 6003 HPV tests performed in 5,227 women were positive, and 141 women who had a positive HPV test (with negative for intraepithelial lesion or malignancy [NILM] or inflammation, or ASC-US and LSIL cytology, but no lesions on colposcopy, or absence of dysplasia on histology) repeated the HPV test at least once. Of these 141 women, 6 were diagnosed with high-grade squamous intraepithelial lesion (HSIL) during the follow-up period. All cases of HSIL were diagnosed after the second HPV test.

Conclusion: This study shows that, at cervical cancer screening, all women testing positive for HPV regardless of Pap smear result should be referred to colposcopy.
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http://dx.doi.org/10.31557/APJCP.2021.22.6.1907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418856PMC
June 2021

Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells.

Nat Commun 2021 05 26;12(1):3155. Epub 2021 May 26.

McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada.

Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.
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http://dx.doi.org/10.1038/s41467-021-23329-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155185PMC
May 2021

Engineered human cardiac microtissues: The state-of-the-(he)art.

Stem Cells 2021 Aug 15;39(8):1008-1016. Epub 2021 Apr 15.

Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.

Due to the integration of recent advances in stem cell biology, materials science, and engineering, the field of cardiac tissue engineering has been rapidly progressing toward developing more accurate functional 3D cardiac microtissues from human cell sources. These engineered tissues enable screening of cardiotoxic drugs, disease modeling (eg, by using cells from specific genetic backgrounds or modifying environmental conditions) and can serve as novel drug development platforms. This concise review presents the most recent advances and improvements in cardiac tissue formation, including cardiomyocyte maturation and disease modeling.
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http://dx.doi.org/10.1002/stem.3376DOI Listing
August 2021

A 3-D human model of complex cardiac arrhythmias.

Acta Biomater 2021 09 10;132:149-161. Epub 2021 Mar 10.

Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Canada; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada. Electronic address:

Cardiac arrhythmias impact over 12 million people globally, with an increasing incidence of acquired arrhythmias. Although animal models have shed light onto fundamental arrhythmic mechanisms, species-specific differences and ethical concerns remain. Current human models using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) either lack the higher order tissue organization of the heart or implement unreliable arrhythmia induction techniques. Our goal was to develop a robust model of acquired arrhythmia by disrupting cardiomyocyte cell-cell signaling - one of the hallmarks of complex arrhythmias. Human 3D microtissues were generated by seeding hydrogel-embedded hiPSC-CMs and cardiac fibroblasts into an established microwell system designed to enable active and passive force assessment. Cell-cell signaling was disrupted using methyl-beta cyclodextrin (MBCD), previously shown to disassemble cardiac gap junctions. We demonstrate that arrhythmias were progressive and present in all microtissues within 5 days of treatment. Arrhythmic tissues exhibited reduced conduction velocity, an increased number of distinct action potentials, and reduced action potential cycle length. Arrhythmic tissues also showed significant reduction in contractile force generation, increased beating frequency, and increased passive tension and collagen deposition, in line with fibrosis. A subset of tissues with more complex arrhythmias exhibited 3D spatial differences in action potential propagation. Pharmacological and electrical defibrillation was successful. Transcriptomic data indicated an enrichment of genes consistent with cardiac arrhythmias. MBCD removal reversed the arrhythmic phenotype, resulting in synchronicity despite not resolving fibrosis. This innovative & reliable human-relevant 3D acquired arrhythmia model shows potential for improving our understanding of arrhythmic action potential conduction and furthering therapeutic development. STATEMENT OF SIGNIFICANCE: This work describes a 3D human model of cardiac arrhythmia-on-a-chip with high reproducibility, fidelity, and extensive functional applicability. To mimic in vivo conditions, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts from healthy controls were combined in a biocompatible fibrin hydrogel and seeded between two deflectable polymeric rods. Using the innate functional properties of this 3D model as well as advanced optical imaging techniques we demonstrated dramatic changes in contraction rate, synchronicity, and electrophysiological conduction in arrhythmic tissues relative to controls. Taken together, these data demonstrate the distinctive potential of this new model for pathophysiological studies, and for arrhythmia drug testing applications.
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http://dx.doi.org/10.1016/j.actbio.2021.03.004DOI Listing
September 2021

Prenatal diagnosis of fibular aplasia-tibial campomelia-oligosyndactyly syndrome: Two case reports and review of the literature.

J Clin Ultrasound 2021 Jul 16;49(6):625-629. Epub 2020 Dec 16.

Pathology Laboratory of CGC Genetics/Centro de Genética Clínica, Porto, Portugal.

Fibular aplasia-tibial campomelia-oligosyndactyly also known as FATCO syndrome is a rare condition characterized by fibular aplasia, shortening and anterior bowing of the lower limb at the tibia with overlying soft tissue dimpling and oligosyndactyly. Its etiology is currently unknown, but there is a male predominance. There are less than 30 cases reported in the literature but only three with prenatal diagnosis. We report two cases of FATCO syndrome with prenatal lower limb malformation diagnosis. Identification of the ultrasound findings of this condition in the prenatal stages allows an adequate parental counselling regarding the clinical features, prognosis, and potential treatments.
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http://dx.doi.org/10.1002/jcu.22969DOI Listing
July 2021

[Patent blue V dye anaphylaxis: a case report and literature review].

Braz J Anesthesiol 2020 Nov-Dec;70(6):662-666. Epub 2020 Nov 2.

Hospital Dr. Nélio Mendonça, Funchal, Portugal.

Background: Anaphylaxis is a constant perioperative concern due to the exposure to several agents capable of inducing hypersensitivity reactions. Patent blue V (PBV), also known as Sulfan Blue, a synthetic dye used in sentinel node research in breast surgery, is responsible for 0.6% of reported anaphylactic conditions. We present a case of a 49-year-old female patient who underwent left breast tumorectomy with sentinel lymph node staging using PBV and experienced an anaphylactic reaction.

Methods: We conducted a literature search through PubMed for case reports, case series, reviews, and systematic reviews since 2005 with the keywords "anaphylaxis" and "patent blue". We then included articles found in these publications' reference sections.

Results: We found 12 relevant publications regarding this topic. The main findings are summarized, with information regarding the clinical presentation, management, and investigation protocol. Hypotension is the most common clinical manifestation. The presentation is usually delayed when compared with anaphylaxis from other agents, and cutaneous manifestations are occasionally absent. Patients may have had previous exposure to the dye, used also as a food, clothes and drug colorant.

Conclusion: The diagnosis of anaphylaxis in patients under sedation or general anesthesia may be difficult due to particularities of the perioperative context. According to the published literature, the presentation of the reaction is similar in most cases and a heightened clinical sense is key to address the situation appropriately. Finding the agent responsible for the allergic reaction is of paramount importance to prevent future episodes.
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http://dx.doi.org/10.1016/j.bjan.2020.05.005DOI Listing
October 2021

Blueberry Consumption Challenges Hepatic Mitochondrial Bioenergetics and Elicits Transcriptomics Reprogramming in Healthy Wistar Rats.

Pharmaceutics 2020 Nov 14;12(11). Epub 2020 Nov 14.

Institute of Pharmacology & Experimental Therapeutics & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

An emergent trend of blueberries' (BB) "prophylactic" consumption, due to their phytochemicals' richness and well-known health-promoting claims, is widely scaled-up. However, the benefits arising from BB indiscriminate intake remains puzzling based on incongruent preclinical and human data. To provide a more in-depth elucidation and support towards a healthier and safer consumption, we conducted a translation-minded experimental study in healthy Wistar rats that consumed BB in a juice form (25 g/kg body weight (BW)/day; 14 weeks' protocol). Particular attention was paid to the physiological adaptations succeeding in the gut and liver tissues regarding the acknowledged BB-induced metabolic benefits. Systemically, BB boosted serum antioxidant activity and repressed the circulating levels of 3-hydroxybutyrate (3-HB) ketone bodies and 3-HB/acetoacetate ratio. Moreover, BB elicited increased fecal succinic acid levels without major changes on gut microbiota (GM) composition and gut ultra-structural organization. Remarkably, an accentuated hepatic mitochondrial bioenergetic challenge, ensuing metabolic transcriptomic reprogramming along with a concerted anti-inflammatory pre-conditioning, was clearly detected upon long-term consumption of BB phytochemicals. Altogether, the results disclosed herein portray a quiescent mitochondrial-related metabolomics and hint for a unified adaptive response to this nutritional challenge. The beneficial or noxious consequences arising from this dietary trend should be carefully interpreted and necessarily claims future research.
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http://dx.doi.org/10.3390/pharmaceutics12111094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697217PMC
November 2020

Transplanted microvessels improve pluripotent stem cell-derived cardiomyocyte engraftment and cardiac function after infarction in rats.

Sci Transl Med 2020 09;12(562)

Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON M5G 1L7, Canada.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer an unprecedented opportunity to remuscularize infarcted human hearts. However, studies have shown that most hiPSC-CMs do not survive after transplantation into the ischemic myocardial environment, limiting their regenerative potential and clinical application. We established a method to improve hiPSC-CM survival by cotransplanting ready-made microvessels obtained from adipose tissue. Ready-made microvessels promoted a sixfold increase in hiPSC-CM survival and superior functional recovery when compared to hiPSC-CMs transplanted alone or cotransplanted with a suspension of dissociated endothelial cells in infarcted rat hearts. Microvessels showed unprecedented persistence and integration at both early (~80%, week 1) and late (~60%, week 4) time points, resulting in increased vessel density and graft perfusion, and improved hiPSC-CM maturation. These findings provide an approach to cell-based therapies for myocardial infarction, whereby incorporation of ready-made microvessels can improve functional outcomes in cell replacement therapies.
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http://dx.doi.org/10.1126/scitranslmed.aax2992DOI Listing
September 2020

Diet-induced rodent models of obesity-related metabolic disorders-A guide to a translational perspective.

Obes Rev 2020 12 20;21(12):e13081. Epub 2020 Jul 20.

Institute of Pharmacology and Experimental Therapeutics, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Diet is a critical element determining human health and diseases, and unbalanced food habits are major risk factors for the development of obesity and related metabolic disorders. Despite technological and pharmacological advances, as well as intensification of awareness campaigns, the prevalence of metabolic disorders worldwide is still increasing. Thus, novel therapeutic approaches with increased efficacy are urgently required, which often depends on cellular and molecular investigations using robust animal models. In the absence of perfect rodent models, those induced by excessive consumption of fat and sugars better replicate the key aspects that are the root causes of human metabolic diseases. However, the results obtained using these models cannot be directly compared, particularly because of the use of different dietary protocols, and animal species and strains, among other confounding factors. This review article revisits diet-induced models of obesity and related metabolic disorders, namely, metabolic syndrome, prediabetes, diabetes and nonalcoholic fatty liver disease. A critical analysis focused on the main pathophysiological features of rodent models, as opposed to the criteria defined for humans, is provided as a practical guide with a translational perspective for the establishment of animal models of obesity-related metabolic diseases.
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http://dx.doi.org/10.1111/obr.13081DOI Listing
December 2020

ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities - Role of gut microbiota dysbiosis.

Ageing Res Rev 2020 09 16;62:101123. Epub 2020 Jul 16.

University of Coimbra, Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal. Electronic address:

Coronavirus disease 19 (COVID-19) is a pandemic condition caused by the new coronavirus SARS-CoV-2. The typical symptoms are fever, cough, shortness of breath, evolving to a clinical picture of pneumonia and, ultimately, death. Nausea and diarrhea are equally frequent, suggesting viral infection or transmission via the gastrointestinal-enteric system. SARS-CoV-2 infects human cells by using angiotensin converting enzyme 2 (ACE2) as a receptor, which is cleaved by transmembrane proteases during host cells infection, thus reducing its activities. ACE2 is a relevant player in the renin-angiotensin system (RAS), counterbalancing the deleterious effects of angiotensin II. Furthermore, intestinal ACE2 functions as a chaperone for the aminoacid transporter BAT1. It has been suggested that BAT1/ACE2 complex in the intestinal epithelium regulates gut microbiota (GM) composition and function, with important repercussions on local and systemic immune responses against pathogenic agents, namely virus. Notably, productive infection of SARS-CoV-2 in ACE2 mature human enterocytes and patients' GM dysbiosis was recently demonstrated. This review outlines the evidence linking abnormal ACE2 functions with the poor outcomes (higher disease severity and mortality rate) in COVID-19 patients with pre-existing age-related comorbidities and addresses a possible role for GM dysbiosis. The article culminates with the therapeutics opportunities based on these pathways.
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http://dx.doi.org/10.1016/j.arr.2020.101123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365123PMC
September 2020

Inflammasome Activation by CD8 T Cells from Patients with Cutaneous Leishmaniasis Caused by Leishmania braziliensis in the Immunopathogenesis of the Disease.

J Invest Dermatol 2021 01 13;141(1):209-213.e2. Epub 2020 Jun 13.

Fiocruz-BA, Instituto Gonçalo Moniz, Salvador, Bahia, Brazil; Faculdade de Medicina da Universidade Federal da Bahia, Salvador, Bahia, Brazil; Instituto Nacional de Ciência e Tecnologia de Instituto de Investigação de Imunologia (Conselho Nacional de Pesquisa/Ministério da Ciência e Tecnologia), São Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.05.106DOI Listing
January 2021

Unbalanced production of LTB/PGE driven by diabetes increases susceptibility to cutaneous leishmaniasis.

Emerg Microbes Infect 2020 Dec;9(1):1275-1286

Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil.

Poorly controlled diabetes mellitus leads to several comorbidities, including susceptibility to infections. Hyperglycemia increases phagocyte responsiveness, however immune cells from people with diabetes show inadequate antimicrobial functions. We and others have shown that aberrant production of leukotriene B (LTB) is detrimental to host defense in models of bacterial infection. Here, we will unveil the consequences of high glucose in the outcome of skin infection in people with diabetes and determine the role of LTB in human phagocytes. We show that diabetes leads to higher systemic levels of LTB, IL-6 and TNF-α in cutaneous leishmaniasis. Only LTB correlated with blood glucose levels and healing time in diabetes comorbidity. Skin lesions of people with leishmaniasis and diabetes exhibit increased neutrophil and amastigote numbers. Monocyte-derived macrophages from these individuals showed higher loads, reduced production of Reactive Oxygen Species and unbalanced LTB/PGE ratio. Our data reveal a systemic inflammation driven by diabetes comorbidity in opposition to a local reduced capacity to resolve infection and a worse disease outcome.
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http://dx.doi.org/10.1080/22221751.2020.1773744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473187PMC
December 2020

Crescent-Like Lesions as an Early Signature of Nephropathy in a Rat Model of Prediabetes Induced by a Hypercaloric Diet.

Nutrients 2020 Mar 25;12(4). Epub 2020 Mar 25.

Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

Diabetic nephropathy (DN) is a major microvascular complication of diabetes. Obesity and hyperlipidemia, fueled by unhealthy food habits, are risk factors to glomerular filtration rate (GFR) decline and DN progression. Several studies recommend that diabetic patients should be screened early (in prediabetes) for kidney disease, in order to prevent advanced stages, for whom the current interventions are clearly inefficient. This ambition greatly depends on the existence of accurate early biomarkers and novel molecular targets, which only may arise with a more thorough knowledge of disease pathophysiology. We used a rat model of prediabetes induced by 23 weeks of high-sugar/high-fat (HSuHF) diet to characterize the phenotype of early renal dysfunction and injury. When compared with the control animals, HSuHF-treated rats displayed a metabolic phenotype compatible with obese prediabetes, displaying impaired glucose tolerance and insulin sensitivity, along with hypertriglyceridemia, and lipid peroxidation. Despite unchanged creatinine levels, the prediabetic animals presented glomerular crescent-like lesions, accompanied by increased kidney Oil-Red-O staining, triglycerides content and mRNA expression of IL-6 and iNOS. This model of HSuHF-induced prediabetes can be a useful tool to study early features of DN, namely crescent-like lesions, an early signature that deserves in-depth elucidation.
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http://dx.doi.org/10.3390/nu12040881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230605PMC
March 2020

Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy.

Nutrients 2020 Jan 18;12(1). Epub 2020 Jan 18.

Institute of Pharmacology & Experimental Therapeutics, & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

Unhealthy dietary habits are major modifiable risk factors for the development of type 2 diabetes mellitus, a metabolic disease with increasing prevalence and serious consequences. Microvascular complications of diabetes, namely diabetic peripheral neuropathy (DPN), retinopathy (DR), and nephropathy (DN), are associated with high morbidity rates and a heavy social and economic burden. Currently, available therapeutic options to counter the evolution of diabetic microvascular complications are clearly insufficient, which strongly recommends further research. Animal models are essential tools to dissect the molecular mechanisms underlying disease progression, to unravel new therapeutic targets, as well as to evaluate the efficacy of new drugs and/or novel therapeutic approaches. However, choosing the best animal model is challenging due to the large number of factors that need to be considered. This is particularly relevant for models induced by dietary modifications, which vary markedly in terms of macronutrient composition. In this article, we revisit the rodent models of diet-induced DPN, DR, and DN, critically comparing the main features of these microvascular complications in humans and the criteria for their diagnosis with the parameters that have been used in preclinical research using rodent models, considering the possible need for factors which can accelerate or aggravate these conditions.
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http://dx.doi.org/10.3390/nu12010250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019796PMC
January 2020

Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing.

Biomaterials 2020 03 31;233:119741. Epub 2019 Dec 31.

Toronto General Hospital Research Institute, University Health Network, 101 College St., Toronto, ON, M5G 1L7, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, Canada; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada. Electronic address:

While interstitial fibrosis plays a significant role in heart failure, our understanding of disease progression in humans is limited. To address this limitation, we have engineered a cardiac-fibrosis-on-a-chip model consisting of a microfabricated device with live force measurement capabilities using co-cultured human cardiac fibroblasts and pluripotent stem cell-derived cardiomyocytes. Transforming growth factor-β was used as a trigger for fibrosis. Here, we have reproduced the classic hallmarks of fibrosis-induced heart failure including high collagen deposition, increased tissue stiffness, BNP secretion, and passive tension. Force of contraction was significantly decreased in fibrotic tissues that displayed a transcriptomic signature consistent with human cardiac fibrosis/heart failure. Treatment with an anti-fibrotic drug decreased tissue stiffness and BNP secretion, with corresponding changes in the transcriptomic signature. This model represents an accessible approach to study human heart failure in vitro, and allows for testing anti-fibrotic drugs while facilitating the real-time assessment of cardiomyocyte function.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119741DOI Listing
March 2020

Endothelium-mediated contributions to fibrosis.

Semin Cell Dev Biol 2020 05 29;101:78-86. Epub 2019 Nov 29.

University Health Network, Toronto General Hospital Research Institute, 101 College St., Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada. Electronic address:

Fibrosis, characterized by abnormal and excessive deposition of extracellular matrix, results in compromised tissue and organ structure. This can lead to reduced organ function and eventual failure. Although activated fibroblasts, called myofibroblasts, are considered the central players in fibrosis, the contribution of endothelial cells to the inception and progression of fibrosis has become increasingly recognized. Endothelial cells can contribute to fibrosis by acting as a source of myofibroblasts via endothelial-mesenchymal transition (EndoMT), or by becoming senescent, by secretion of profibrotic mediators and pro-inflammatory cytokines, chemokines and exosomes, promoting the recruitment of immune cells, and by participating in vascular rarefaction and decreased angiogenesis. In this review, we provide an overview of the different aspects of fibrosis in which endothelial cells have been implicated.
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http://dx.doi.org/10.1016/j.semcdb.2019.10.015DOI Listing
May 2020

The yin and yang faces of the mitochondrial deacetylase sirtuin 3 in age-related disorders.

Ageing Res Rev 2020 01 15;57:100983. Epub 2019 Nov 15.

Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal. Electronic address:

Aging, the most important risk factor for many of the chronic diseases affecting Western society, is associated with a decline in mitochondrial function and dynamics. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that has emerged as a key regulator of fundamental processes which are frequently dysregulated in aging and related disorders. This review highlights recent advances and controversies regarding the yin and yang functions of SIRT3 in metabolic, cardiovascular and neurodegenerative diseases, as well as the use of SIRT3 modulators as a therapeutic strategy against those disorders. Although most studies point to a protective role upon SIRT3 activation, there are conflicting findings that need a better elucidation. The discovery of novel SIRT3 modulators with higher selectivity together with the assessment of the relative importance of different SIRT3 enzymatic activities and the relevance of crosstalk between distinct sirtuin isoforms will be pivotal to validate SIRT3 as a useful drug target for the prevention and treatment of age-related diseases.
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http://dx.doi.org/10.1016/j.arr.2019.100983DOI Listing
January 2020

Correction to: Type I Diabetes Delays Perfusion and Engraftment of 3D Constructs by Impinging on Angiogenesis; Which can be Rescued by Hepatocyte Growth Factor Supplementation.

Cell Mol Bioeng 2019 Oct 17;12(5):541-542. Epub 2019 Sep 17.

Toronto General Hospital Research Institute, University Health Network, 101 College St., MaRS, TMDT 3-904, Toronto, ON M5G 1L7 Canada.

[This corrects the article DOI: 10.1007/s12195-019-00574-3.].
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http://dx.doi.org/10.1007/s12195-019-00595-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816639PMC
October 2019

Type I Diabetes Delays Perfusion and Engraftment of 3D Constructs by Impinging on Angiogenesis; Which can be Rescued by Hepatocyte Growth Factor Supplementation.

Cell Mol Bioeng 2019 Oct 21;12(5):443-454. Epub 2019 May 21.

Toronto General Hospital Research Institute, University Health Network, 101 College St., MaRS, TMDT 3-904, Toronto, ON M5G 1L7 Canada.

Introduction: The biggest bottleneck for cell-based regenerative therapy is the lack of a functional vasculature to support the grafts. This problem is exacerbated in diabetic patients, where vessel growth is inhibited. To address this issue, we aim to identify the causes of poor vascularization in 3D engineered tissues in diabetes and to reverse its negative effects.

Methods: We used 3D vascularized constructs composed of microvessel fragments containing all cells present in the microcirculation, embedded in collagen type I hydrogels. Constructs were either cultured or implanted subcutaneously in non-diabetic or in a type I diabetic (streptozotocin-injected) mouse model. We used qPCR, ELISA, immunostaining, FACs and co-culture assays to characterize the effect of diabetes in engineered constructs.

Results: We demonstrated in 3D vascularized constructs that perivascular cells secrete hepatocyte growth factor (HGF), driving microvessel sprouting. Blockage of HGF or HGF receptor signaling in 3D constructs prevented vessel sprouting. Moreover, HGF expression in 3D constructs is downregulated in diabetes; while no differences were found in HGF receptor, VEGF or VEGF receptor expression. Low HGF expression in diabetes delayed the inosculation of graft and host vessels, decreasing blood perfusion and preventing tissue engraftment. Supplementation of HGF in 3D constructs, restored vessel sprouting in a diabetic milieu.

Conclusion: We show for the first time that diabetes affects HGF secretion in microvessels, which in turn prevents the engraftment of engineered tissues. Exogenous supplementation of HGF, restores angiogenic growth in 3D constructs showing promise for application in cell-based regenerative therapies.
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http://dx.doi.org/10.1007/s12195-019-00574-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816716PMC
October 2019

Acromion fracture and lateral angle of the scapula spine: Case report and literature review.

Int J Surg Case Rep 2019 22;60:353-357. Epub 2019 Jun 22.

Goiás Federal University, Brazil.

Introduction: Scapular fractures are uncommon and correspond to 0.5-1% of all body fractures. The study objective was to present a rare case report of a fracture (lateral acromion and angle of the scapula spine) and review of the literature on which will greatly contribute to diagnosis and treatment.

Presentation Of Case: A 74-year-old female patient with comminuted fracture of the acromial process and lateral angle of the spine of the scapula with subacromial space. The patient underwent surgical treatment with open reduction and use of blocked plaque, two plain Steinmann wires 2.0 and local bone graft.

Discussion: Segmental fracture of acromion and spine of the scapula needs early diagnosis for the proper treatment. In our case report, the patient presented fracture of the acromion and lateral angle of the spine of the scapula, classified as Ogawa 1 and 3; Kunt 3; and AO A1, respectively.

Conclusion: Segmental fracture of the acromion and lateral angle of the spine of the scapula with subacromial space reduction requires surgical intervention in order to avoid secondary complications. Early diagnosis favors better prognosis.
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http://dx.doi.org/10.1016/j.ijscr.2019.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614114PMC
June 2019

The Protective Role of Adiponectin for Lipoproteins in End-Stage Renal Disease Patients: Relationship with Diabetes and Body Mass Index.

Oxid Med Cell Longev 2019 18;2019:3021785. Epub 2019 Feb 18.

UCIBIO/REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.

Cardiovascular disease (CVD) events are the main causes of death in end-stage renal disease (ESRD) patients on dialysis. The number and severity of CVD events remain inappropriate and difficult to explain by considering only the classic CVD risk factors. Our aim was to clarify the changes and the relationship of lipoprotein subfractions with other CVD risk factors, namely, body mass index (BMI) and adipokines, inflammation and low-density lipoprotein (LDL) oxidation, and the burden of the most prevalent comorbidities, diabetes mellitus (DM) and hypertension (HT). We studied 194 ESRD patients on dialysis and 22 controls; lipid profile, including lipoprotein subpopulations and oxidized LDL (oxLDL), C-reactive protein (CRP), adiponectin, leptin, and paraoxonase 1 activity were evaluated. Compared to controls, patients presented significantly lower levels of cholesterol, high-density lipoprotein cholesterol (HDLc), LDLc, oxLDL, and intermediate and small HDL and higher triglycerides, CRP, adiponectin, large HDL, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein- (IDL) B. Adiponectin levels correlated positively with large HDL and negatively with intermediate and small HDL, oxLDL/LDLc, and BMI; patients with DM ( = 17) and with DM+HT ( = 70), as compared to patients without DM or HT ( = 69) or only with HT ( = 38), presented significantly higher oxLDL, oxLDL/LDLc, and leptin and lower adiponectin. Obese patients ( = 45), as compared to normoponderal patients ( = 81), showed lower HDLc, adiponectin, and large HDL and significantly higher leptin, VLDL, and intermediate and small HDL. In ESRD, the higher adiponectin seems to favor atheroprotective HDL modifications and protect LDL particles from oxidative atherogenic changes. However, in diabetic and obese patients, adiponectin presents the lowest values, oxLDL/LDLc present the highest ones, and the HDL profile is the more atherogenic. Our data suggest that the coexistence of DM and adiposity in ESRD patients on dialysis contributes to a higher CVD risk, as showed by their lipid and adipokine profiles.
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http://dx.doi.org/10.1155/2019/3021785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397972PMC
April 2019

Molecular Aspects of Dendritic Cell Activation in Leishmaniasis: An Immunobiological View.

Front Immunol 2019 22;10:227. Epub 2019 Feb 22.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.

Dendritic cells (DC) are a diverse group of leukocytes responsible for bridging innate and adaptive immunity. Despite their functional versatility, DCs exist primarily in two basic functional states: immature and mature. A large body of evidence suggests that upon interactions with pathogens, DCs undergo intricate cellular processes that culminate in their activation, which is paramount to the orchestration of effective immune responses against a parasites. Herein we offer a concise review of the emerging hallmarks of DCs activation in leishmaniasis as well as a comprehensive discussion of the following underlying molecular events: DC- interaction, antigen uptake, costimulatory molecule expression, parasite ability to affect DC migration, antigen presentation, metabolic reprogramming, and epigenetic alterations.
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http://dx.doi.org/10.3389/fimmu.2019.00227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401646PMC
September 2020

Therapeutic Options Targeting Oxidative Stress, Mitochondrial Dysfunction and Inflammation to Hinder the Progression of Vascular Complications of Diabetes.

Front Physiol 2018 17;9:1857. Epub 2019 Jan 17.

Center for Neurosciences and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal.

Type 2 diabetes mellitus is a leading cause of morbidity and mortality worldwide, given its serious associated complications. Despite constant efforts and intensive research, an effective, ubiquitous treatment still eludes the scientific community. As such, the identification of novel avenues of research is key to the potential discovery of this evasive "silver bullet." We focus on this review on the matter of diabetic injury to endothelial tissue and some of the pivotal underlying mechanisms, including hyperglycemia and hyperlipidemia evoked oxidative stress and inflammation. In this sense, we revisited the most promising therapeutic interventions (both non-pharmacological and antidiabetic drugs) targeting oxidative stress and inflammation to hinder progression of vascular complications of diabetes. This review article gives particular attention to the relevance of mitochondrial function, an often ignored and understudied organelle in the vascular endothelium. We highlight the importance of mitochondrial function and number homeostasis in diabetic conditions and discuss the work conducted to address the aforementioned issue by the use of various therapeutic strategies. We explore here the functional, biochemical and bioenergetic alterations provoked by hyperglycemia in the endothelium, from elevated oxidative stress to inflammation and cell death, as well as loss of tissue function. Furthermore, we synthetize the literature regarding the current and promising approaches into dealing with these alterations. We discuss how known agents and therapeutic behaviors (as, for example, metformin, dietary restriction or antioxidants) can restore normality to mitochondrial and endothelial function, preserving the tissue's function and averting the aforementioned complications.
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http://dx.doi.org/10.3389/fphys.2018.01857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344610PMC
January 2019
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