Publications by authors named "Rosa Fernandes"

93 Publications

Serum Proteomics Reveals Alterations in Protease Activity, Axon Guidance, and Visual Phototransduction Pathways in Infants With Exposure to Zika Virus Without Congenital Zika Syndrome.

Front Cell Infect Microbiol 2020 18;10:577819. Epub 2020 Nov 18.

GlycoProteomics Laboratory, Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

In 2015, ZIKV infection attracted international attention during an epidemic in the Americas, when neurological disorders were reported in infants who had their mothers exposed to ZIKV during pregnancy. World Health Organization (WHO) epidemiological data show that 5 to 15% of neonates exposed to ZIKV in the uterus have complications included in abnormalities related to Congenital Zika Syndrome (CZS). The risk of complications after birth is not well documented, however, clinical evidence shows that 6% of infants exposed to ZIKV during pregnancy have complications present at birth, and this rate rises to 14% when medical monitoring is performed in all exposed infants, regardless of birth condition. Thus, the evaluation and monitoring of all exposed infants are of foremost importance as the development of late complications has been increasingly supported by clinical evidence. The identification of changes in protein profile of infants exposed to ZIKV without CZS could provide valuable findings to better understand molecular changes in this cohort. Here, we use a shotgun-proteomics approach to investigate alterations in the serum of infants without CZS symptoms but exposed to intrauterine ZIKV (ZIKV) compared to unexposed controls (CTRL). A complex pattern of differentially expressed proteins was identified, highlighting the dysregulation of proteins involved in axon orientation, visual phototransduction, and global protease activity in children exposed to ZIKV without CZS. These data support the importance of monitoring children exposed to ZIKV during gestation and without early CZS symptoms. Our study is the first to assess molecular evidence of possible late disorders in children victims of the ZIKV outbreak in the Americas. We emphasize the importance of medical monitoring of symptomatic and asymptomatic children, as apparently unexplained late neurological and eye disorders may be due to intrauterine ZIKV exposure.
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http://dx.doi.org/10.3389/fcimb.2020.577819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708324PMC
November 2020

Refractory chronic urticaria in adults: clinical characterization and predictors of severity.

Allergy Asthma Clin Immunol 2020 Nov 11;16(1):97. Epub 2020 Nov 11.

Allergy and Clinical Immunology Departement, Centro Hospitalar E Universitário de Coimbra, Coimbra, Portugal.

Background: Chronic urticaria (CU) is defined as recurrent urticaria lasting for more than 6 weeks.

Objectives: We aimed to characterize the phenotypes of patients with CU refractory to standard dose anti-H1 antihistamine treatment and search for clinical predictors of poor disease control.

Methods: Retrospective collection of data regarding clinical characteristics, comorbidities, treatment, and disease control of all adult refractory CU patients presenting to the Allergy and Immunology Department during 1 year.

Results: Sixty-one adult patients were included, 74% females, average age 44.5 years (18 to 84 years old). Most patients (78.7%) had initiated CU less than 1 year before enrolment. Chronic spontaneous urticaria (CSU) accounted for 55.7% of the patients, CSU associated with chronic inducible urticaria (CIndU) as a comorbidity for 44.3%, and angioedema was present in 55.7%. Medically-confirmed psychiatric disorders were present in 78.7%. Complementary diagnostic tests were performed in cases with more severe presentation (UAS7 ≥ 28 and/or UCT < 12) or with longer evolution (> 1 year), corresponding to 42 tested patient. Evidence for autoimmunity (positive anti-thyroid peroxidase antibodies, anti-nuclear antibodies or autologous serum test) was found in 45.2% (n = 19/42), and high C-reactive protein was present in 14.3% (n = 6/42), half of these also had positive antinuclear antibodies. Forty-six patients (75.4%) had at least one significant exacerbation, requiring medical appointment, emergency room, hospitalization or job absenteeism. The number of exacerbations correlated with the presence of angioedema (p = 0.022), with a recent diagnosis (< 1 year), and with higher UAS7 severity (p = 0.006). Although ClndU was associated with poor symptom control (p = 0.022), it was also associated with less exacerbations requiring medical observation or hospitalization (p = 0.015). All patients were using antihistamines and 21.3% (n = 13) of them were also under treatment with omalizumab, ciclosporine or montelukast for disease control.

Conclusions: Autoimmunity can affect about half of the patients with severe or long-term CU. UAS7 and angioedema are associated with disease exacerbations. UAS7 and UCT presented unequal accuracy, with UAS7 better associating with the occurrence of exacerbations and treatment doses. Patients with refractory CU frequently present psychiatric disorders. Accurate diagnostic tests, namely autoimmune parameters and inflammatory markers, should be recommended in some individual cases.
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http://dx.doi.org/10.1186/s13223-020-00496-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661155PMC
November 2020

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

Lights and Shadows of TORCH Infection Proteomics.

Genes (Basel) 2020 08 5;11(8). Epub 2020 Aug 5.

Glycoproteomics Laboratory, Department of Parasitology, University of Sao Paulo, Sao Paulo 05508-000, Brazil.

Congenital abnormalities cause serious fetal consequences. The term TORCH is used to designate the most common perinatal infections, where: (T) refers to toxoplasmosis, (O) means "others" and includes syphilis, varicella-zoster, parvovirus B19, zika virus (ZIKV), and malaria among others, (R) refers to rubella, (C) relates to cytomegalovirus infection, and (H) to herpes simplex virus infections. Among the main abnormalities identified in neonates exposed to congenital infections are central nervous system (CNS) damage, microcephaly, hearing loss, and ophthalmological impairment, all requiring regular follow-up to monitor its progression. Protein changes such as mutations, post-translational modifications, abundance, structure, and function may indicate a pathological condition before the onset of the first symptoms, allowing early diagnosis and understanding of a particular disease or infection. The term "proteomics" is defined as the science that studies the proteome, which consists of the total protein content of a cell, tissue or organism in a given space and time, including post-translational modifications (PTMs) and interactions between proteins. Currently, quantitative bottom-up proteomic strategies allow rapid and high throughput characterization of complex biological mixtures. Investigating proteome modulation during host-pathogen interaction helps in elucidating the mechanisms of infection and in predicting disease progression. This "molecular battle" between host and pathogen is a key to identify drug targets and diagnostic markers. Here, we conducted a survey on proteomic techniques applied to congenital diseases classified in the terminology "TORCH", including toxoplasmosis, ZIKV, malaria, syphilis, human immunodeficiency virus (HIV), herpes simplex virus (HSV) and human cytomegalovirus (HCVM). We have highlighted proteins and/or protein complexes actively involved in the infection. Most of the proteomic studies reported have been performed in cell line models, and the evaluation of tissues (brain, muscle, and placenta) and biofluids (plasma, serum and urine) in animal models is still underexplored. Moreover, there are a plethora of studies focusing on the pathogen or the host without considering the triad mother-fetus-pathogen as a dynamic and interconnected system.
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http://dx.doi.org/10.3390/genes11080894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464470PMC
August 2020

Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy.

Antioxidants (Basel) 2020 Aug 4;9(8). Epub 2020 Aug 4.

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

Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation of new blood vessels, which are fragile and prone to leaking. This disease, if left untreated, may result in severe vision loss and eventually legal blindness. Although there are some available treatment options for DR, most of them are targeted to the advanced stages of the disease, have some adverse effects, and many patients do not adequately respond to the treatment, which demands further research. Oxidative stress and low-grade inflammation are closely associated processes that play a critical role in the development of DR. Retinal cells communicate with each other or with another one, using cell junctions, adhesion contacts, and secreted soluble factors that can act in neighboring or long-distance cells. Another mechanism of cell communication is via secreted extracellular vesicles (EVs), through exchange of material. Here, we review the current knowledge on deregulation of cell-to-cell communication through EVs, discussing the changes in miRNA expression profiling in body fluids and their role in the development of DR. Thereafter, current and promising therapeutic agents for preventing the progression of DR will be discussed.
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http://dx.doi.org/10.3390/antiox9080705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463887PMC
August 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

Cellular Imprinting Proteomics Assay: A Novel Method for Detection of Neural and Ocular Disorders Applied to Congenital Zika Virus Syndrome.

J Proteome Res 2020 11 4;19(11):4496-4515. Epub 2020 Aug 4.

GlycoProteomics Laboratory, Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

Congenital Zika syndrome was first described due to increased incidence of congenital abnormalities associated with Zika virus (ZIKV) infection. Since the eye develops as part of the embryo central nervous system (CNS) structure, it becomes a specialized compartment able to display symptoms of neurodegenerative diseases and has been proposed as a noninvasive approach to the early diagnosis of neurological diseases. Ocular lesions result from defects that occurred during embryogenesis and can become apparent in newborns exposed to ZIKV. Furthermore, the absence of microcephaly cannot exclude the occurrence of ocular lesions and other CNS manifestations. Considering the need for surveillance of newborns and infants with possible congenital exposure, we developed a method termed cellular imprinting proteomic assay (CImPA) to evaluate the ocular surface proteome specific to infants exposed to ZIKV during gestation compared to nonexposure. CImPA combines surface cells and fluid capture using membrane disks and a large-scale quantitative proteomics approach, which allowed the first-time report of molecular alterations such as neutrophil degranulation, cell death signaling, ocular and neurological pathways, which are associated with ZIKV infection with and without the development of congenital Zika syndrome, CZS. Particularly, infants exposed to ZIKV during gestation and without early clinical symptoms could be detected using the CImPA method. Lastly, this methodology has broad applicability as it could be translated in the study of several neurological diseases to identify novel diagnostic biomarkers. Data are available via ProteomeXchange with identifier PXD014038.
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http://dx.doi.org/10.1021/acs.jproteome.0c00320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640952PMC
November 2020

Microglia Contribution to the Regulation of the Retinal and Choroidal Vasculature in Age-Related Macular Degeneration.

Cells 2020 05 14;9(5). Epub 2020 May 14.

Retinal Dysfunction and Neuroinflammation Lab, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

The retina is a highly metabolically active tissue with high-level consumption of nutrients and oxygen. This high metabolic demand requires a properly developed and maintained vascular system. The retina is nourished by two systems: the central retinal artery that supplies the inner retina and the choriocapillaris that supplies the outer retina and retinal pigment epithelium (RPE). Pathological neovascularization, characterized by endothelial cell proliferation and new vessel formation, is a common hallmark in several retinal degenerative diseases, including age-related macular degeneration (AMD). A limited number of studies have suggested that microglia, the resident immune cells of the retina, have an important role not only in the pathology but also in the formation and physiology of the retinal vascular system. Here, we review the current knowledge on microglial interaction with the retinal vascular system under physiological and pathological conditions. To do so, we first highlight the role of microglial cells in the formation and maintenance of the retinal vasculature system. Thereafter, we discuss the molecular signaling mechanisms through which microglial cells contribute to the alterations in retinal and choroidal vasculatures and to the neovascularization in AMD.
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http://dx.doi.org/10.3390/cells9051217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290930PMC
May 2020

Caveolin-1 Modulation Increases Efficacy of a Galacto-Conjugated Phthalocyanine in Bladder Cancer Cells Resistant to Photodynamic Therapy.

Mol Pharm 2020 06 12;17(6):2145-2154. Epub 2020 May 12.

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

Photodynamic therapy (PDT) has demonstrated encouraging anticancer therapeutic results, but the current clinically approved photosensitizers (PSs) are not ideal in the treatment of bladder cancer. Conventional PSs have low selectivity to the bladder tumor tissue and induce toxicity or bystander effects on nontumor urothelium. Previous studies demonstrated that the use of galactose-photosensitizer (PS) conjugates is a more selective method of delivering PDT-mediated toxicity due to their ability to recognize carbohydrate-binding domains overexpressed in bladder tumors. Using patient-derived bladder tumor specimens cultured and bladder cancer cell lines with different PDT sensitivity, we find that a galactose-phthalocyanine (PcGal) accumulates in bladder tumors expressing galactose-binding proteins and internalizes through an endocytic process. The endocytosis mechanism is cell line-dependent. In HT-1376 bladder cancer lines resistant to PDT, depletion of caveolin-1-the main structural protein of caveolae structures-increased the amount of sugar-binding proteins, i.e. GLUT1, at the cell membrane resulting in an improved PcGal uptake and PDT efficacy. These data show the potential of cultures of bladder cancer, that ideally could mimic the original microenvironment, in screening galacto-PDT agents. Additionally, our studies demonstrate that PDT efficacy in bladder cancer depends on the endocytic mechanisms that regulate PS accumulation and internalization in cancer cells.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00298DOI Listing
June 2020

Synthesis, Characterization and Photodynamic Activity against Bladder Cancer Cells of Novel Triazole-Porphyrin Derivatives.

Molecules 2020 Mar 31;25(7). Epub 2020 Mar 31.

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.

Novel triazole-porphyrin derivatives (TZ-PORs) were synthesized through the Heck reaction and then incorporated into polyvinylpyrrolidone (PVP) micelles. After verifying that this incorporation did not compromise the photophysical and chemical features of TZ-PORs as photosensitizers, the phototoxicity of the formulations towards cancer cells was screened. Biological studies show high photodynamic activity of all PVP-TZ-POR formulations against a bladder cancer cell line with a particular highlight to PVP-TZ-POR and that are able to significantly reduce HT-1376 cell viability, while they had no effect on control ARPE-19 cells.
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http://dx.doi.org/10.3390/molecules25071607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180931PMC
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

Highly Efficient Singlet Oxygen Generators Based on Ruthenium Phthalocyanines: Synthesis, Characterization and in vitro Evaluation for Photodynamic Therapy.

Chemistry 2020 Feb 10;26(8):1697. Epub 2020 Jan 10.

Departamento de Química Orgánica, Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049, Madrid, Spain.

Invited for the cover of this issue is the group of Torres at the University of Madrid. The image of the cover of this issue depicts cancer cells being destroyed by reactive singlet oxygen produced by ruthenium phthalocyanine glycoconjugates under red light. The work, developed at the Universities of Madrid, Aveiro, Lisbon and Coimbra, describes ruthenium phthalocyanines as powerful bladder cancer PDT agents. Read the full text of the article at 10.1002/chem.201903546.
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http://dx.doi.org/10.1002/chem.201905549DOI Listing
February 2020

Impression Cytology Is a Non-invasive and Effective Method for Ocular Cell Retrieval of Zika Infected Babies: Perspectives in OMIC Studies.

Front Mol Neurosci 2019 5;12:279. Epub 2019 Dec 5.

Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States.

Importance: Non-invasive techniques for retrieving ocular surface cells from babies infected by zika virus (ZIKV) during the gestational period remain to be determined.

Objectives: The aim of this study was to describe an optimized impression cytology method for the isolation of viable cells from Zika infected babies with and without Congenital Zika Syndrome (CZS) in satisfactory amount and quality to enable easy adoption in the field and application in the context of genomic and molecular approaches.

Design Settings And Participants: Ocular surface samples were obtained with a hydrophilic nitrocellulose membrane (through optimized impression cytology method) from twelve babies referred to the Pediatric Service of the Antonio Pedro Hospital, Universidade Federal Fluminense (UFF), Niteroi, Rio de Janeiro, Brazil. After an authorized written informed consent from the parents, samples were collected from both eyes of 12 babies (4 babies with maternal ZIKV exposure during gestation and presence of clinical signs which included ocular abnormalities and microcephaly; 4 babies with maternal ZIKV exposure during gestation but no clinical signs; and 4 unaffected control babies with negative PCR for Zika virus and without clinical signs). Cells were used for microscopy analyses and evaluated for their suitability for downstream molecular applications in transcriptomic and proteomic experiments.

Results: Our optimized impression cytology protocol enabled the capture of a considerable number of viable cells. The microscopic features of the conjunctival epithelial cells were described by both direct analysis of the membrane-attached cells and analysis of cytospinned captured cells using several staining procedures. Epithelial basal, polyhedral and goblet cells were clearly identified in all groups. All cases of ZIKV infected babies showed potential morphological alterations (cell keratinization, pyknosis, karyolysis, anucleation, and vacuolization). Molecular approaches were also performed in parallel. Genomic DNA and RNA were successfully isolated from all samples to enable the establishment of transcriptomic and proteomic studies.

Conclusions And Relevance: Our method proved to be a suitable, fast, and non-invasive tool to obtain ocular cell preparations from babies with and without Zika infection. The method yielded sufficient cells for detailed morphological and molecular analyses of samples. We discuss perspectives for the application of impression cytology in the context of ZIKV studies in basic and clinical research.
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http://dx.doi.org/10.3389/fnmol.2019.00279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907025PMC
December 2019

Complete Multilineage CD4 Expression Defect Associated With Warts Due to an Inherited Homozygous CD4 Gene Mutation.

Front Immunol 2019 8;10:2502. Epub 2019 Nov 8.

Allergy and Clinical Immunology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Idiopathic T-CD4 lymphocytopenia (ICL) is a rare and heterogeneous syndrome characterized by opportunistic infections due to reduced CD4 T-lymphocytes (<300 cells/μl or <20% T-cells) in the absence of HIV infection and other primary causes of lymphopenia. Molecular testing of ICL has revealed defects in genes not specific to CD4 T-cells, with pleiotropic effects on other cell types. Here we report for the first time an absolute CD4 lymphocytopenia (<0.01 CD4 T-cells/μl) due to an autosomal recessive CD4 gene mutation that completely abrogates CD4 protein expression on the surface membrane of T-cells, monocytes, and dendritic cells. A 45-year-old female born to consanguineous parents consulted because of exuberant, relapsing, and treatment-refractory warts on her hands and feet since the age of 10 years, in the absence of other recurrent infections or symptoms. Serological studies were negative for severe infections, including HIV 1/2, HTLV-1, and syphilis, but positive for CMV and EBV. Blood analysis showed the absence of CD4 T-cells (<0.01%) with repeatedly increased counts of B-cells, naïve CD8 T-lymphocytes, and particularly, CD4/CD8 double-negative (DN) TCRαβ TCRγδ T-cells (30% of T-cells; 400 cells/μl). Flow cytometric staining of CD4 using monoclonal antibodies directed against five different epitopes, located in two different domains of the protein, confirmed no cell surface membrane or intracytoplasmic expression of CD4 on T-cells, monocytes, and dendritic cells but normal soluble CD4 plasma levels. DN T-cells showed a phenotypic and functional profile similar to normal CD4 T-cells as regards expression of maturation markers, T-helper and T-regulatory chemokine receptors, TCRvβ repertoire, and cytokine production against polyclonal and antigen-specific stimuli. Sequencing of the gene revealed a homozygous (splicing) mutation affecting the last bp on intron 7-8, leading to deletion of the juxtamembrane and intracellular domains of the protein and complete abrogation of CD4 expression on the cell membrane. These findings support previous studies in CD4 KO mice suggesting that surrogate DN helper and regulatory T-cells capable of supporting antigen-specific immune responses are produced in the absence of CD4 signaling and point out the need for better understanding the role of CD4 on thymic selection and the immune response.
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http://dx.doi.org/10.3389/fimmu.2019.02502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856949PMC
October 2020

Highly Efficient Singlet Oxygen Generators Based on Ruthenium Phthalocyanines: Synthesis, Characterization and in vitro Evaluation for Photodynamic Therapy.

Chemistry 2020 Feb 7;26(8):1789-1799. Epub 2019 Nov 7.

Departamento de Química Orgánica, Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049, Madrid, Spain.

The synthesis of ruthenium(II) phthalocyanines (RuPcs) endowed with one carbohydrate unit-that is, glucose, galactose and mannose-and a dimethylsulfoxide (DMSO) ligand at the two axial coordination sites, respectively, is described. Two series of compounds, one unsubstituted at the periphery, and the other one bearing eight PEG chains at the isoindole meta-positions, have been prepared. The presence of the axial DMSO unit significantly increases the phthalocyanine singlet oxygen quantum yields, related to other comparable RuPcs. The compounds have been evaluated for PDT treatment in bladder cancer cells. In vitro studies have revealed high phototoxicity for RuPcs unsubstituted at their periphery. The phototoxicity of PEG-substituted RuPcs has been considerably improved by repeated light irradiation. The choice of the axial carbohydrate introduced little differences in the cellular uptake for both series of photosensitizers, but the phototoxic effects were considerably higher for compounds bearing mannose units.
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http://dx.doi.org/10.1002/chem.201903546DOI Listing
February 2020

The dipeptidyl peptidase 4 inhibitor sitagliptin improves oxidative stress and ameliorates glomerular lesions in a rat model of type 1 diabetes.

Life Sci 2019 Oct 6;234:116738. Epub 2019 Aug 6.

Institute of Pharmacology and Experimental Therapeutics & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; CNC.IBILI Consortium, University of Coimbra, Coimbra, Portugal. Electronic address:

Aims: Oxidative stress has been linked to the development and progression of diabetic nephropathy (DN). The present study evaluated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates glomerular lesions and oxidative stress evoked by chronic hyperglycemia, by a mechanism independent of insulin secretion and glycemia normalization.

Main Methods: A rat model of DN caused by streptozotocin injection was established and the effects of sitagliptin (5 mg/kg/day) were evaluated after two weeks of treatment.

Key Findings: Sitagliptin treatment did not change body weight, glycemic and lipid profiles. However, histopathological observation revealed that sitagliptin attenuates diabetes-induced glomerular lesions on diabetic rats. Sitagliptin also ameliorated the increase in DPP-4 content and promoted the stabilization of GLP-1 in the diabetic kidney. Furthermore, sitagliptin treatment significantly attenuated the increase of free-radical formation and the decrease of antioxidant defenses, attenuating therefore the oxidative stress in the kidneys of diabetic animals.

Significance: The results suggest that sitagliptin treatment alleviates kidney oxidative stress in type 1 diabetic rats, which could play a key role in reducing the progression of DN.
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http://dx.doi.org/10.1016/j.lfs.2019.116738DOI Listing
October 2019

Electrochemical Immunosensor for TNFα-Mediated Inflammatory Disease Screening.

ACS Chem Neurosci 2019 06 18;10(6):2676-2682. Epub 2019 Apr 18.

International Iberian Nanotechnology Laboratory , Braga 4715-330 , Portugal.

Inflammation associated with cancer, neurodegenerative, ocular, and autoimmune diseases has a considerable impact on public health. Tumor necrosis factor alpha (TNFα) is a key mediator of inflammatory responses, responsible for many of the systemic manifestations during the inflammatory process. Thus, inhibition of TNFα is a commonplace practice in the treatment of these disorders. Successful therapy requires the ability to determine the appropriate dose of anti-TNFα drugs to be administered in a timely manner, based on circulating TNFα levels. In this Letter, we report the development of an immunosensor technology able to quantify TNFα at the picogram level in relevant human body fluids, holding the potential to early detect inflammation  and monitor TNFα levels during treatment, enabling TNFα-targeted treatments to be tailored according to the immune status of an individual patient. This immunosensor technology is significantly more rapid and sensitive than conventional enzyme linked immunosorbent assays, maintaining high specificity and requiring small sample volumes. These features might also be advantageous in the context of personalized medicine, as this analytical platform can deliver advanced diagnostics and reduce clinical burden.
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http://dx.doi.org/10.1021/acschemneuro.9b00036DOI Listing
June 2019

Zika Virus Impairs Neurogenesis and Synaptogenesis Pathways in Human Neural Stem Cells and Neurons.

Front Cell Neurosci 2019 15;13:64. Epub 2019 Mar 15.

Department of Parasitology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil.

Growing evidences have associated Zika virus (ZIKV) infection with congenital malformations, including microcephaly. Nonetheless, signaling mechanisms that promote the disease outcome are far from being understood, affecting the development of suitable therapeutics. In this study, we applied shotgun mass spectrometry (MS)-based proteomics combined with cell biology approaches to characterize altered molecular pathways on human neuroprogenitor cells (NPC) and neurons derived from induced pluripotent stem cells infected by ZIKV-BR strain, obtained from the 2015 Brazilian outbreak. Furthermore, ZIKV-BR infected NPCs showed unique alteration of pathways involved in neurological diseases, cell death, survival and embryonic development compared to ZIKV-AF, showing a human adaptation of the Brazilian viral strain. Besides, infected neurons differentiated from NPC presented an impairment of neurogenesis and synaptogenesis processes. Taken together, these data explain that CNS developmental arrest observed in Congenital Zika Syndrome is beyond neuronal cell death.
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http://dx.doi.org/10.3389/fncel.2019.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436085PMC
March 2019

Liver proteomics unravel the metabolic pathways related to Feed Efficiency in beef cattle.

Sci Rep 2019 03 29;9(1):5364. Epub 2019 Mar 29.

Department of Veterinary Medicine, School of Animal Science and Food Engineering, University of São Paulo, Pirassununga, 13635-900, Brazil.

Improving nutrient utilization efficiency is essential for livestock, given the current scenario of increasing demand for animal protein and sustainable resource use. In this context, understanding the biology of feed efficiency (FE) in beef cattle allows the development of markers for identification and selection of best animals for animal production. Thus, 98 young Nellore bulls were evaluated for FE and at the end of the experiment liver samples from six High Feed Efficient (HFE) and six Low Feed Efficient (LFE) animals were collected for protein extraction, digestion and analysis by HPLC-MS/MS. Data were analyzed for differential abundant proteins (DAPs), protein networks, and functional enrichment. Serum endotoxin was also quantified. We found 42 DAPs and 3 protein networks significantly related to FE. The main pathways associated with FE were: microbial metabolism; biosynthesis of fatty acids, amino acids and vitamins; glycolysis/gluconeogenesis; xenobiotic metabolism and; antigen processing and presentation. Serum endotoxins were significantly higher in LFE animals supporting the results. Therefore, the findings presented here confirmed the altered hepatic metabolism and pronounced hepatic inflammation in LFE animals supporting that the increased bacterial load is at least in part responsible for the hepatic lesions and inflammation in LFE animals.
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http://dx.doi.org/10.1038/s41598-019-41813-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441086PMC
March 2019

Multicharged Phthalocyanines as Selective Ligands for G-Quadruplex DNA Structures.

Molecules 2019 Feb 18;24(4). Epub 2019 Feb 18.

QOPNA & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.

The stabilization of G-Quadruplex DNA structures by ligands is a promising strategy for telomerase inhibition in cancer therapy since this enzyme is responsible for the unlimited proliferation of cancer cells. To assess the potential of a compound as a telomerase inhibitor, selectivity for quadruplex over duplex DNA is a fundamental attribute, as the drug must be able to recognize quadruplex DNA in the presence of a large amount of duplex DNA, in the cellular nucleus. By using different spectroscopic techniques, such as ultraviolet-visible, fluorescence and circular dichroism, this work evaluates the potential of a series of multicharged phthalocyanines, bearing four or eight positive charges, as G-Quadruplex stabilizing ligands. This work led us to conclude that the existence of a balance between the number and position of the positive charges in the phthalocyanine structure is a fundamental attribute for its selectivity for G-Quadruplex structures over duplex DNA structures. Two of the studied phthalocyanines, one with four peripheral positive charges (ZnPc1) and the other with less exposed eight positive charges (ZnPc4) showed high selectivity and affinity for G-Quadruplex over duplex DNA structures and were able to accumulate in the nucleus of UM-UC-3 bladder cancer cells.
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http://dx.doi.org/10.3390/molecules24040733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412362PMC
February 2019

Photoimmunoconjugates: novel synthetic strategies to target and treat cancer by photodynamic therapy.

Org Biomol Chem 2019 03;17(10):2579-2593

CQE, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.

Photodynamic therapy (PDT) combines a photosensitizer (PS) with the physical energy of non-ionizing light to trigger cell death pathways. PDT has potential as a therapeutic modality to be used in alternative or in combination with other conventional cancer treatment protocols (e.g. surgery, chemotherapy and radiotherapy). Still, due to the lack of specificity of the current PSs to target the tumor cells, several studies have exploited their conjugation with targeting moieties. PSs conjugated with antibodies (Abs) or their fragments, able to bind antigens overexpressed in the tumors, have demonstrated potential in PDT of tumors. This review provides an overview of the most recent advances on photoimmunoconjugates (PICs) for cancer PDT, which involve the first and second-generation PSs conjugated to Abs. This is an update of our previous review "Antibodies armed with photosensitizers: from chemical synthesis to photobiological applications", published in 2015 in Org. Biomol. Chem.
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http://dx.doi.org/10.1039/c8ob02902dDOI Listing
March 2019

Author Correction: Snake Venom Extracellular vesicles (SVEVs) reveal wide molecular and functional proteome diversity.

Sci Rep 2018 Oct 23;8(1):15908. Epub 2018 Oct 23.

GlycoProteomics Laboratory, Department of Parasitology, ICB, University of São Paulo, São Paulo, Brazil.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-33284-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198013PMC
October 2018

Diabetic gut microbiota dysbiosis as an inflammaging and immunosenescence condition that fosters progression of retinopathy and nephropathy.

Biochim Biophys Acta Mol Basis Dis 2019 07 1;1865(7):1876-1897. Epub 2018 Oct 1.

Institute of Pharmacology & Experimental Therapeutics, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, CNC.IBILI Consortium & CIBB Consortium, University of Coimbra, Coimbra, Portugal. Electronic address:

The increased prevalence of type 2 diabetes mellitus (T2DM) and life expectancy of diabetic patients fosters the worldwide prevalence of retinopathy and nephropathy, two major microvascular complications that have been difficult to treat with contemporary glucose-lowering medications. The gut microbiota (GM) has become a lively field research in the last years; there is a growing recognition that altered intestinal microbiota composition and function can directly impact the phenomenon of ageing and age-related disorders. In fact, human GM, envisaged as a potential source of novel therapeutics, strongly modulates host immunity and metabolism. It is now clear that gut dysbiosis and their products (e.g. p-cresyl sulfate, trimethylamine‑N‑oxide) dictate a secretory associated senescence phenotype and chronic low-grade inflammation, features shared in the physiological process of ageing ("inflammaging") as well as in T2DM ("metaflammation") and in its microvascular complications. This review provides an in-depth look on the crosstalk between GM, host immunity and metabolism. Further, it characterizes human GM signatures of elderly and T2DM patients. Finally, a comprehensive scrutiny of recent molecular findings (e.g. epigenetic changes) underlying causal relationships between GM dysbiosis and diabetic retinopathy/nephropathy complications is pinpointed, with the ultimate goal to unravel potential pathophysiological mechanisms that may be explored, in a near future, as personalized disease-modifying therapeutic approaches.
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http://dx.doi.org/10.1016/j.bbadis.2018.09.032DOI Listing
July 2019

Integrated Proteomics Reveals Apoptosis-related Mechanisms Associated with Placental Malaria.

Mol Cell Proteomics 2019 02 21;18(2):182-199. Epub 2018 Sep 21.

From the ‡Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo São Paulo, Brazil;

Malaria in pregnancy is a public health concern in malaria-endemic areas. Accumulation of maternal immune cells in the placenta and increased levels of inflammatory cytokines caused by sequestration of -infected erythrocytes have been associated to poor neonatal outcomes, including low birth weight because of fetal growth restriction. Little is known about the molecular changes occurring in a -infected placenta that has developed placental malaria during pregnancy but had the parasites cleared by pharmacological treatment (past infection). We conducted an integrated proteome, phosphoproteome and glycoproteome analysis in past -infected placentas aiming to find molecular changes associated with placental malaria. A total of 2946 proteins, 1733 -linked glycosites and 4100 phosphosites were identified and quantified in this study, disclosing overrepresented processes related to oxidative stress, protein folding and regulation of apoptosis in past-infected placentas Moreover, AKT and ERK signaling pathways activation, together with clinical data, were further correlated to an increased apoptosis in past-infected placentas. This study showed apoptosis-related mechanisms associated with placental malaria that can be further explored as therapeutic target against adverse pregnancy outcomes.
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http://dx.doi.org/10.1074/mcp.RA118.000907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356084PMC
February 2019

Distinct urinary glycoprotein signatures in prostate cancer patients.

Oncotarget 2018 Sep 4;9(69):33077-33097. Epub 2018 Sep 4.

Instituto de Ciências Biomédicas, Departamento de Parasitologia, Universidade de São Paulo, USP, São Paulo, Brazil.

Novel biomarkers are needed to complement prostate specific antigen (PSA) in prostate cancer (PCa) diagnostic screening programs. Glycoproteins represent a hitherto largely untapped resource with a great potential as specific and sensitive tumor biomarkers due to their abundance in bodily fluids and their dynamic and cancer-associated glycosylation. However, quantitative glycoproteomics strategies to detect potential glycoprotein cancer markers from complex biospecimen are only just emerging. Here, we describe a glycoproteomics strategy for deep quantitative mapping of - and -glycoproteins in urine with a view to investigate the diagnostic value of the glycoproteome to discriminate PCa from benign prostatic hyperplasia (BPH), two conditions that remain difficult to clinically stratify. Total protein extracts were obtained, concentrated and digested from urine of six PCa patients (Gleason score 7) and six BPH patients. The resulting peptide mixtures were TMT-labeled and mixed prior to a multi-faceted sample processing including hydrophilic interaction liquid chromatography (HILIC) and titanium dioxide SPE based enrichment, endo-/exoglycosidase treatment and HILIC-HPLC pre-fractionation. The isolated - and -glycopeptides were detected and quantified using high resolution mass spectrometry. We accurately quantified 729 -glycoproteins spanning 1,310 unique N-glycosylation sites and observed 954 and 965 unique intact - and -glycopeptides, respectively, across the two disease conditions. Importantly, a panel of 56 intact N-glycopeptides perfectly discriminated PCa and BPH (ROC: AUC = 1). This study has generated a panel of intact glycopeptides that has a potential for PCa detection.
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http://dx.doi.org/10.18632/oncotarget.26005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145689PMC
September 2018

A Galactose Dendritic Silicon (IV) Phthalocyanine as a Photosensitizing Agent in Cancer Photodynamic Therapy.

Chempluschem 2018 Sep;83(9):855-860

QOPNA, Department of Chemistry, University of Aveiro Campus Universitário de Santiago, 3810-193, Aveiro, Portugal.

Two protected galacto-dendritic units have been axially coordinated to the central ion of a silicon(IV) phthalocyanine to afford SiPcPGal containing four units of galactose per macrocycle. These biological moieties provided better solubility in aqueous medium and a sensitizer with higher absorption peaks at 680-690 nm. The photodynamic activity of SiPcPGal was evaluated against UM-UC-3 human bladder cancer cell line and the results were compared with the activity of the reported SiPcPGal and SiPc(OH) . SiPcPGal had a better uptake and it was a better toxicity inducer than SiPcPGal and SiPc(OH) owing to its four galactose units, protected by isopropylidene groups, which can act as targeted micelles.
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http://dx.doi.org/10.1002/cplu.201800370DOI Listing
September 2018

Proteome-Wide Analysis of Trypanosoma cruzi Exponential and Stationary Growth Phases Reveals a Subcellular Compartment-Specific Regulation.

Genes (Basel) 2018 Aug 15;9(8). Epub 2018 Aug 15.

Department of Parasitology, Institute of Biomedical Sciences, University of Sao Paulo, 05508-900 Sao Paulo, Brazil.

, the etiologic agent of Chagas disease, cycles through different life stages characterized by defined molecular traits associated with the proliferative or differentiation state. In particular, epimastigotes are the replicative forms that colonize the intestine of the Triatomine insect vector before entering the stationary phase that is crucial for differentiation into metacyclic trypomastigotes, which are the infective forms of mammalian hosts. The transition from proliferative exponential phase to quiescent stationary phase represents an important step that recapitulates the early molecular events of metacyclogenesis, opening new possibilities for understanding this process. In this study, we report a quantitative shotgun proteomic analysis of the epimastigote in the exponential and stationary growth phases. More than 3000 proteins were detected and quantified, highlighting the regulation of proteins involved in different subcellular compartments. Ribosomal proteins were upregulated in the exponential phase, supporting the higher replication rate of this growth phase. Autophagy-related proteins were upregulated in the stationary growth phase, indicating the onset of the metacyclogenesis process. Moreover, this study reports the regulation of N-terminally acetylated proteins during growth phase transitioning, adding a new layer of regulation to this process. Taken together, this study reports a proteome-wide rewiring during transit from the replicative exponential phase to the stationary growth phase, which is the preparatory phase for differentiation.
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http://dx.doi.org/10.3390/genes9080413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115888PMC
August 2018

Snake Venom Extracellular vesicles (SVEVs) reveal wide molecular and functional proteome diversity.

Sci Rep 2018 08 13;8(1):12067. Epub 2018 Aug 13.

GlycoProteomics Laboratory, Department of Parasitology, ICB, University of São Paulo, São Paulo, Brazil.

Proteins constitute almost 95% of snake venom's dry weight and are produced and released by venom glands in a solubilized form during a snake bite. These proteins are responsible for inducing several pharmacological effects aiming to immobilize and initiate the pre-digestion of the prey. This study shows that proteins can be secreted and confined in snake venom extracellular vesicles (SVEVs) presenting a size distribution between 50 nm and 500 nm. SVEVs isolated from lyophilized venoms collected from four different species of snakes (Agkistrodon contortrix contortrix, Crotalus atrox, Crotalus viridis and Crotalus cerberus oreganus) were analyzed by mass spectrometry-based proteomic, which allowed the identification of proteins belonging to eight main functional protein classes such as SVMPs, serine proteinases, PLA, LAAO, 5'nucleotidase, C-type lectin, CRISP and Disintegrin. Biochemical assays indicated that SVEVs are functionally active, showing high metalloproteinase and fibrinogenolytic activity besides being cytotoxic against HUVEC cells. Overall, this study comprehensively depicts the protein composition of SVEVs for the first time. In addition, the molecular function of some of the described proteins suggests a central role for SVEVs in the cytotoxicity of the snake venom and sheds new light in the envenomation process.
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http://dx.doi.org/10.1038/s41598-018-30578-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089973PMC
August 2018

Sweet Stress: Coping With Vascular Dysfunction in Diabetic Retinopathy.

Front Physiol 2018 13;9:820. Epub 2018 Jul 13.

Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Oxidative stress plays key roles in the pathogenesis of retinal diseases, such as diabetic retinopathy. Reactive oxygen species (ROS) are increased in the retina in diabetes and the antioxidant defense system is also compromised. Increased ROS stimulate the release of pro-inflammatory cytokines, promoting a chronic low-grade inflammation involving various signaling pathways. An excessive production of ROS can lead to retinal endothelial cell injury, increased microvascular permeability, and recruitment of inflammatory cells at the site of inflammation. Recent studies have started unraveling the complex crosstalk between retinal endothelial cells and neuroglial cells or leukocytes, via both cell-to-cell contact and secretion of cytokines. This crosstalk is essential for the maintenance of the integrity of retinal vascular structure. Under diabetic conditions, an aberrant interaction between endothelial cells and other resident cells of the retina or invading inflammatory cells takes place in the retina. Impairment in the secretion and flow of molecular signals between different cells can compromise the retinal vascular architecture and trigger angiogenesis. In this review, the synergistic contributions of redox-inflammatory processes for endothelial dysfunction in diabetic retinopathy will be examined, with particular attention paid to endothelial cell communication with other retinal cells.
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http://dx.doi.org/10.3389/fphys.2018.00820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053590PMC
July 2018

Allergic contact dermatitis caused by dexpanthenol-Probably a frequent allergen.

Contact Dermatitis 2018 Nov 16;79(5):276-280. Epub 2018 Jul 16.

Dermatology Department, Centro Hospitalar Universitário de Coimbra, Centro Hospitalar e Universitário de Coimbra (CHUC), Coimbra, Portugal.

Background: Panthenol (synonym: dexpanthenol), the alcohol analogue of panthothenic acid, is frequently included in moisturizers, wound-healing agents, and other cosmetics, and has been shown to be responsible for allergic contact dermatitis (ACD).

Objectives: To evaluate the frequency of ACD caused by dexpanthenol, and to characterize reactive patients.

Methods: We retrospectively reviewed the files of patients patch tested between 2009 and 2017 in the Department of Dermatology of the Coimbra's University Hospital and describe patients who reacted to dexpanthenol 5% pet., tested initially in a cosmetic/vehicle series and in the last 3 years in consecutive patients.

Results: Among 2171 patients, 26 (1.2%) had positive patch test reactions to dexpanthenol, mostly patients tested for chronic eczema (88.5%, n = 23), either widespread (5), or localized to the hands (5), face (4), or legs (7). Relevance could be traced in 20 patients (76.9%), related to the use of Bepanthene cream (15), moisturizers (3), topical medications (1), and a shampoo (1). Twenty-five of 26 patients (96.2%) reacted to several other allergens, mostly ingredients of cosmetic or pharmaceutical products.

Conclusions: Although ACD caused by dexpanthenol is considered to be rare, it may be frequently overlooked. As we found a relatively high frequency of relevant cases, in agreement with a previous study, the inclusion of dexpanthenol in patch test series, at least in cosmetic and topical drug series, is encouraged.
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http://dx.doi.org/10.1111/cod.13054DOI Listing
November 2018