Publications by authors named "Flavio Reis"

111 Publications

Is Gut Microbiota Dysbiosis a Predictor of Increased Susceptibility to Poor Outcome of COVID-19 Patients? An Update.

Microorganisms 2020 Dec 28;9(1). Epub 2020 Dec 28.

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

The scientific knowledge already attained regarding the way severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells and the clinical manifestations and consequences for Coronavirus Disease 2019 (COVID-19) patients, especially the most severe cases, brought gut microbiota into the discussion. It has been suggested that intestinal microflora composition plays a role in this disease because of the following: (i) its relevance to an efficient immune system response; (ii) the fact that 5-10% of the patients present gastrointestinal symptoms; and (iii) because it is modulated by intestinal angiotensin-converting enzyme 2 (ACE2) (which is the virus receptor). In addition, it is known that the most severely affected patients (those who stay longer in hospital, who require intensive care, and who eventually die) are older people with pre-existing cardiovascular, metabolic, renal, and pulmonary diseases, the same people in which the prevalence of gut microflora dysbiosis is higher. The COVID-19 patients presenting poor outcomes are also those in which the immune system's hyperresponsiveness and a severe inflammatory condition (collectively referred as "cytokine storm") are particularly evident, and have been associated with impaired microbiota phenotype. In this article, we present the evidence existing thus far that may suggest an association between intestinal microbiota composition and the susceptibility of some patients to progress to severe stages of the disease.
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http://dx.doi.org/10.3390/microorganisms9010053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824665PMC
December 2020

New Potential Biomarkers for Chronic Kidney Disease Management-A Review of the Literature.

Int J Mol Sci 2020 Dec 22;22(1). Epub 2020 Dec 22.

UCIBIO\REQUIMTE, Laboratory of Biochemistry, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.

The prevalence of chronic kidney disease (CKD) is increasing worldwide, and the mortality rate continues to be unacceptably high. The biomarkers currently used in clinical practice are considered relevant when there is already significant renal impairment compromising the early use of potentially successful therapeutic interventions. More sensitive and specific biomarkers to detect CKD earlier on and improve patients' prognoses are an important unmet medical need. The aim of this review is to summarize the recent literature on new promising early CKD biomarkers of renal function, tubular lesions, endothelial dysfunction and inflammation, and on the auspicious findings from metabolomic studies in this field. Most of the studied biomarkers require further validation in large studies and in a broad range of populations in order to be implemented into routine CKD management. A panel of biomarkers, including earlier biomarkers of renal damage, seems to be a reasonable approach to be applied in clinical practice to allow earlier diagnosis and better disease characterization based on the underlying etiologic process.
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http://dx.doi.org/10.3390/ijms22010043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793089PMC
December 2020

Lactation as a programming window for metabolic syndrome.

Eur J Clin Invest 2020 Dec 22:e13482. Epub 2020 Dec 22.

Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.

The concept of developmental origins of health and disease (DOHaD) was initially supported by the low birth weight and higher risk of developing cardiovascular disease in adult life, caused by nutrition restriction during foetal development. However, other programming windows have been recognized in the last years, namely lactation, infancy, adolescence and even preconception. Although the concept has been developed in order to study the impact of foetal calorie restriction in adult life, it is now recognized that maternal overweight during programming windows is also harmful to the offspring. This article explores and summarizes the current knowledge about the impact of maternal obesity and obesogenic diets during lactation in the metabolic programming towards the development of metabolic syndrome in the adult life. The impact of maternal obesity and obesogenic diets in milk quality is discussed, including the alterations in specific micro and macronutrients, as well as the impact of such alterations in the development of metabolic syndrome-associated features in the newborn, such as insulin resistance and adiposity. Moreover, the impact of milk quality and formula feeding in infants' gut microbiota, immune system maturation and in the nutrient-sensing mechanisms, namely those related to gut hormones and leptin, are also discussed under the current knowledge.
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http://dx.doi.org/10.1111/eci.13482DOI Listing
December 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

Gut Microbiota Dysbiosis-Immune Hyperresponse-Inflammation Triad in Coronavirus Disease 2019 (COVID-19): Impact of Pharmacological and Nutraceutical Approaches.

Microorganisms 2020 Oct 1;8(10). Epub 2020 Oct 1.

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

Coronavirus Disease 2019 (COVID-19) is a pandemic infection caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients present a complex clinical picture that, in severe cases, evolves to respiratory, hepatic, gastrointestinal, and neurological complications, and eventually death. The underlying pathophysiological mechanisms are complex and multifactorial and have been summarized as a hyperresponse of the immune system that originates an inflammatory/cytokine storm. In elderly patients, particularly in those with pre-existing cardiovascular, metabolic, renal, and pulmonary disorders, the disease is particularly severe, causing prolonged hospitalization at intensive care units (ICU) and an increased mortality rate. Curiously, the same populations have been described as more prone to a gut microbiota (GM) dysbiosis profile. Intestinal microflora plays a major role in many metabolic and immune functions of the host, including to educate and strengthen the immune system to fight infections, namely of viral origin. Notably, recent studies suggest the existence of GM dysbiosis in COVID-19 patients. This review article highlights the interplay between the triad GM dysbiosis-immune hyperresponse-inflammation in the individual resilience/fragility to SARS-CoV-2 infection and presents the putative impact of pharmacological and nutraceutical approaches on the triumvirate, with focus on GM.
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http://dx.doi.org/10.3390/microorganisms8101514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601735PMC
October 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

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

Technical Challenges in Lung Transplantation of Kartagener Syndrome Recipients: A Unique Team Experience With 12 Patients.

Transplant Proc 2020 Jun 14;52(5):1384-1387. Epub 2020 Apr 14.

Lung Transplantation Division, Thoracic Surgery Department, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Lung Transplantation Department, Hospital Israelita Albert Einstein, São Paulo, Brazil.

Kartagener syndrome (KS) is a rare congenital disorder related to bronchiectasis, chronic sinusitis, and situs inversus, predisposing patients to recurrent respiratory infections that can evolve to end-stage lung disease; lung transplantation (LTx) is one of the therapeutic options. This study highlights some concerns in this group of patients, mainly related to the difficulty of performing the transplantation in recipients with suppurative disease and situs inversus. We conducted a retrospective analysis of all KS patients who underwent LTx at 2 national reference centers by the same LTx team. During 29 years of analysis, we performed 12 cases of bilateral sequential LTx in KS patients, representing 2.4% of all Ltx that we performed. Special perioperative care is needed, including vascular access sites and lung isolation techniques; operative concerns include the arteriotomy and bronchotomy during the back table preparation of the graft and concern about the length of the arterial and bronchial anastomosis. We found a higher incidence of bronchial complications is this group that had not been previously reported. Bilateral sequential orthotopic LTx is feasible in this group of patients, and more studies are needed to understand possible reasons for the apparent higher incidence of bronchial complications.
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http://dx.doi.org/10.1016/j.transproceed.2020.02.031DOI Listing
June 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

Intraoperative support with venovenous extracorporeal membrane oxygenation for complex thoracic oncologic resection.

J Bras Pneumol 2020 01 20;46(1):e20180416. Epub 2020 Jan 20.

. Divisão de Cirurgia Torácica, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.

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http://dx.doi.org/10.1590/1806-3713/e20180416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462687PMC
January 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

Corrigendum to "Gastrointestinal mucormycosis post lung transplantation" [Braz J Infect Dis 23 (2019) 368-370].

Braz J Infect Dis 2020 Jan - Feb;24(1):92. Epub 2020 Jan 2.

Universidade de São Paulo, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, São Paulo, SP, Brazil.

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http://dx.doi.org/10.1016/j.bjid.2019.12.006DOI Listing
January 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

Dichotomous Sirtuins: Implications for Drug Discovery in Neurodegenerative and Cardiometabolic Diseases.

Trends Pharmacol Sci 2019 12 6;40(12):1021-1039. Epub 2019 Nov 6.

CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB - Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.

Sirtuins (SIRT1-7), a class of NAD-dependent deacylases, are central regulators of metabolic homeostasis and stress responses. While numerous salutary effects associated with sirtuin activation, especially SIRT1, are well documented, other reports show health benefits resulting from sirtuin inhibition. Furthermore, conflicting findings have been obtained regarding the pathophysiological role of specific sirtuin isoforms, suggesting that sirtuins act as 'double-edged swords'. Here, we provide an integrated overview of the different findings on the role of mammalian sirtuins in neurodegenerative and cardiometabolic disorders and attempt to dissect the reasons behind these different effects. Finally, we discuss how addressing these obstacles may provide a better understanding of the complex sirtuin biology and improve the likelihood of identifying effective and selective drug targets for a variety of human disorders.
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http://dx.doi.org/10.1016/j.tips.2019.09.003DOI Listing
December 2019

Beneficial Effects of Dietary Polyphenols on Gut Microbiota and Strategies to Improve Delivery Efficiency.

Nutrients 2019 Sep 13;11(9). Epub 2019 Sep 13.

Department of Biochemistry, University of Allahabad, Allahabad 211002, India.

The human intestine contains an intricate ecological community of dwelling bacteria, referred as gut microbiota (GM), which plays a pivotal role in host homeostasis. Multiple factors could interfere with this delicate balance, including genetics, age, antibiotics, as well as environmental factors, particularly diet, thus causing a disruption of microbiota equilibrium (dysbiosis). Growing evidences support the involvement of GM dysbiosis in gastrointestinal (GI) and extra-intestinal cardiometabolic diseases, namely obesity and diabetes. This review firstly overviews the role of GM in health and disease, then critically reviews the evidences regarding the influence of dietary polyphenols in GM based on preclinical and clinical data, ending with strategies under development to improve efficiency of delivery. Although the precise mechanisms deserve further clarification, preclinical and clinical data suggest that dietary polyphenols present prebiotic properties and exert antimicrobial activities against pathogenic GM, having benefits in distinct disorders. Specifically, dietary polyphenols have been shown ability to modulate GM composition and function, interfering with bacterial quorum sensing, membrane permeability, as well as sensitizing bacteria to xenobiotics. In addition, can impact on gut metabolism and immunity and exert anti-inflammatory properties. In order to overcome the low bioavailability, several different approaches have been developed, aiming to improve solubility and transport of dietary polyphenols throughout the GI tract and deliver in the targeted intestinal regions. Although more research is still needed, particularly translational and clinical studies, the biotechnological progresses achieved during the last years open up good perspectives to, in a near future, be able to improve the use of dietary polyphenols modulating GM in a broad range of disorders characterized by a dysbiotic phenotype.
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http://dx.doi.org/10.3390/nu11092216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770155PMC
September 2019

Gastrointestinal mucormycosis post lung transplantation.

Braz J Infect Dis 2019 Sep - Oct;23(5):368-370. Epub 2019 Aug 30.

Universidade de São Paulo, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, São Paulo, SP, BR.

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http://dx.doi.org/10.1016/j.bjid.2019.07.003DOI Listing
December 2019

SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma.

Cancers (Basel) 2019 Aug 10;11(8). Epub 2019 Aug 10.

LAQV/REQUIMTE, Department of Biological Sciences, Laboratory of Microbiology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.

Half of human cancers harbor mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.
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http://dx.doi.org/10.3390/cancers11081151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721528PMC
August 2019

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

Development of a Healthy Lifestyle Assessment Toolkit for the General Public.

Front Med (Lausanne) 2019 27;6:134. Epub 2019 Jun 27.

Faculty of Medicine, Institute of Pharmacology & Experimental Therapeutics, University of Coimbra, Coimbra, Portugal.

The prevalence of age-related non-communicable chronic diseases has increased worldwide, being the leading causes of morbidity and death in many world regions, including in Europe. Innovative models and strategies focused on preventive care, including early identification of risk factors underlying disease onset and progression, and proper modification of lifestyle habits and behaviors, might contribute to promote quality of life, healthy living and active aging. Healthy Lifestyle Innovative Quarters for Cities and Citizens (HeaLIQs4cities) is an EIT Health-funded project aiming to engage, empower and educate citizens toward healthy lifestyles. One of the major objectives of this project was to develop a toolkit for a rapid and informal assessment of healthy lifestyles, to be used at different levels of care pathways, including in informal public environments. In this paper, we describe the methodology underlying the development of the toolkit, which resulted from the collaboration of an interdisciplinary focus group of academic experts, from medicine, sport sciences, psychology, health economics, and innovative technologies applied to health. The following eight components were included in the toolkit: (1) anthropometric assessment and cardiometabolic parameters; (2) physical activity and exercise; (3) well-being, social cohesion, and functional independence; (4) nutrition; (5) mental health; (6) smoking, drinking, and use of illicit substances; (7) sleep habits and quality; and (8) health and disease. A traffic light rating system indicating the risk score was used (low: green; moderate: yellow; and relevant: orange) for each of the 8 components, together with recommendations for the toolkit users. After completing the reduced version of the toolkit, individuals showing moderate or relevant risk in one or more of the 8 dimensions, were invited to participate in a more detailed assessment (toolkit long version), based on deeper and scientifically validated tools. The toolkit was incorporated in eVida, a web-based platform that focuses on delivering services to personalized health and well-being. The validation of the current toolkit has been applied in wide-ranging public events in three different European Regions. Large scale deployment of the toolkit is expected to profit from the Reference Site Collaborative Network of the European Innovation Partnership on Active and Healthy Aging (EIP on AHA).
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http://dx.doi.org/10.3389/fmed.2019.00134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610478PMC
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

mTOR Signaling in Cardiometabolic Disease, Cancer, and Aging 2018.

Oxid Med Cell Longev 2019;2019:9692528. Epub 2019 Feb 4.

Department of Cellular & Integrative Physiology, and Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

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http://dx.doi.org/10.1155/2019/9692528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378800PMC
August 2019

Hepcidin in chronic kidney disease anemia.

Vitam Horm 2019 6;110:243-264. Epub 2019 Feb 6.

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

Chronic kidney disease (CKD) is associated with several complications that worsen with progression of disease; anemia, disturbances in iron metabolism and inflammation are common features. Inflammatory response starts early, releasing pro-inflammatory cytokines, acute phase reactants and hepcidin. Hepcidin production is modulated by several factors, as hypoxia/anemia, erythropoietin and erythropoiesis products, transferrin saturation (TSAT) and liver iron levels, which are altered in CKD. Treatment of CKD anemia is based on pharmaceutical intervention, with erythropoietic stimulating agents and/or iron supplementation; however, in spite of the erythropoietic benefits, this therapy, on a regular basis, involves risks, namely iron overload. To overcome these risks, some therapeutic approaches are under study to target CKD anemia. Considering the actual alerts about risk of iron overload in dialysis patients, inhibition of hepcidin, the central key player in iron homeostasis, could be a pivotal strategy in the management of CKD anemia.
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http://dx.doi.org/10.1016/bs.vh.2019.01.012DOI Listing
June 2019

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

Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges.

Oxid Med Cell Longev 2018 29;2018:3693625. Epub 2018 Oct 29.

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

The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has a key role in the regulation of a variety of biological processes pivotal for cellular life, aging, and death. Impaired activity of mTOR complexes (mTORC1/mTORC2), particularly mTORC1 overactivation, has been implicated in a plethora of age-related disorders, including human renal diseases. Since the discovery of rapamycin (or sirolimus), more than four decades ago, advances in our understanding of how mTOR participates in renal physiological and pathological mechanisms have grown exponentially, due to both preclinical studies in animal models with genetic modification of some mTOR components as well as due to evidence coming from the clinical experience. The main clinical indication of rapamycin is as immunosuppressive therapy for the prevention of allograft rejection, namely, in renal transplantation. However, considering the central participation of mTOR in the pathogenesis of other renal disorders, the use of rapamycin and its analogs meanwhile developed (rapalogues) everolimus and temsirolimus has been viewed as a promising pharmacological strategy. This article critically reviews the use of mTOR inhibitors in renal diseases. Firstly, we briefly overview the mTOR components and signaling as well as the pharmacological armamentarium targeting the mTOR pathway currently available or in the research and development stages. Thereafter, we revisit the mTOR pathway in renal physiology to conclude with the advances, drawbacks, and challenges regarding the use of mTOR inhibitors, in a translational perspective, in four classes of renal diseases: kidney transplantation, polycystic kidney diseases, renal carcinomas, and diabetic nephropathy.
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http://dx.doi.org/10.1155/2018/3693625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231362PMC
January 2019

Weight loss achieved by bariatric surgery modifies high-density lipoprotein subfractions and low-density lipoprotein oxidation towards atheroprotection.

Clin Biochem 2019 Jan 17;63:46-53. Epub 2018 Oct 17.

UCIBIO\REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia da Universidade do Porto (FFUP), Porto, Portugal. Electronic address:

Objectives: Weight loss achieved by laparoscopic adjustable gastric banding (LAGB) induces an increase in high-density lipoprotein cholesterol (HDLc) but a small effect on low-density lipoprotein (LDL), although changes in their quality (size and composition) are uncertain. Our aim was to study the impact of weight loss, achieved 13-months after LAGB, on inflammation and dyslipidemia, focusing on HDL and LDL subfractions, and oxidized LDL (oxLDL).

Design & Methods: We evaluated standard lipid profile, HDL and LDL subfractions, oxLDL, interleukin (IL)-6 and C-reactive protein (CRP), in twenty obese patients, before (T0) and 13-months after LAGB (T1), and in seventeen healthy controls.

Results: At T1, patients showed lower body weight (12% median weight loss) and anthropometric indices; reduction in TG, atherogenic indices, oxLDL, oxLDL/LDL ratio, CRP and IL-6, and enhancement in HDLc; an increase in large HDL and intermediate HDL subfractions, and a decrease in small HDL subfraction; LDL subfractions were not modified. Percentual change (%Δ) of oxLDL, from T0 to T1, correlated significantly and positively with %Δ of small HDL subfraction and with %Δ of body mass index.

Conclusions: Weight loss induced atheroprotective changes on inflammation, and lipid profile, enhancing larger HDL, the more atheroprotective subfraction, reducing the less protective subclass, small HDL, and reducing oxLDL and oxLDL/LDL ratio. Quality of lipoproteins appears useful cardiovascular risk biomarkers, deserving further studies.
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http://dx.doi.org/10.1016/j.clinbiochem.2018.10.007DOI Listing
January 2019

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

Subtle thinning of retinal layers without overt vascular and inflammatory alterations in a rat model of prediabetes.

Mol Vis 2018 18;24:353-366. Epub 2018 May 18.

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

Purpose: Diabetic retinopathy is a neurovascular disease characterized by increased permeability of the blood-retinal barrier, changes in the neural components of the retina, and low-grade chronic inflammation. Diabetic retinopathy is a major complication of diabetes; however, the impact of a prediabetic state on the retina remains to be elucidated. The aim of this study was to assess possible early retinal changes in prediabetic rats, by evaluating changes in the integrity of the blood-retinal barrier, the retinal structure, neural markers, and inflammatory mediators.

Methods: Several parameters were analyzed in the retinas of Wistar rats that drank high sucrose (HSu; 35% sucrose solution during 9 weeks, the prediabetic animal model) and were compared with those of age-matched controls. The permeability of the blood-retinal barrier was assessed with the Evans blue assay, and the content of the tight junction proteins and neural markers with western blotting. Optical coherence tomography was used to evaluate retinal thickness. Cell loss at the ganglion cell layer was assessed with terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and by evaluating the immunoreactivity of the Brn3a transcription factor. To assess retinal neuroinflammation, the mRNA expression and protein levels of inducible nitric oxide synthase isoform (iNOS), interleukin-1 beta (IL-1β), and tumor necrosis factor (TNF) were evaluated. Iba1 and MHC-II immunoreactivity and translocator protein (TSPO) mRNA levels were assessed to study the microglial number and activation state.

Results: The thickness of the inner retinal layers of the HSu-treated animals decreased. Nevertheless, no apoptotic cells were observed, and no changes in retinal neural markers were detected in the retinas of the HSu-treated animals. No changes were detected in the permeability of the blood-retinal barrier, as well as the tight junction protein content between the HSu-treated rats and the controls. In addition, the inflammatory parameters remained unchanged in the retina despite the tendency for an increase in the number of retinal microglial cells.

Conclusions: In a prediabetic rat model, the retinal structure is affected by the thinning of the inner layers, without overt vascular and inflammatory alterations. The results suggest neuronal dysfunction (thinning of the inner retina) that may precede or anticipate the vascular and inflammatory changes. Subtle structural changes might be viewed as early disturbances in an evolving disease, suggesting that preventive strategies (such as the modification of diet habits) could be applied at this stage, before the progression toward irreversible dysfunction and damage to the retina.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957544PMC
November 2018

Influence of the 6-month physical activity programs on renal function in obese boys.

Pediatr Res 2018 05 11;83(5):1011-1015. Epub 2018 Apr 11.

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

BackgroundWe intended to evaluate the effects of physical activity (PA) programs on renal function in obese boys.MethodsThirty-nine boys participated in one of the following three groups: soccer (SG, n=13), traditional PA (AG, n=13), and sedentary control (CG, n=13). SG and AG were involved in 6-month PA programs, involving three sessions/week for 60-90 min. Anthropometric measurements, body composition, creatinine and cystatin C plasmatic levels, and estimated glomerular filtration rate (eGFR) were evaluated.ResultsAt baseline (n=39), age and lean mass index (LMI) were positively correlated with creatinine levels. After 6 months, both intervention groups decreased the BMI z-score and waist circumference, while the CG increased the body fat percentage (BFP). LMI increased in all the groups. SG presented a small increment in plasma creatinine and a decrease in the eGFR values, using the Schwartz formula. Concerning the cystatin C levels and eGFR values using Filler (cystatin C-based) or Combined Zappitelli (creatinine/cystatin C-based) formulas, no significant changes were observed in any group.ConclusionThe combined Zappitelli formula showed no significant impact of PA on eGFR in obese boys. Although plasma creatinine is significantly influenced by lean body mass, cystatin C is likely to be a more accurate marker of renal function in this population.
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http://dx.doi.org/10.1038/pr.2018.15DOI Listing
May 2018

Discovery of a small-molecule protein kinase Cδ-selective activator with promising application in colon cancer therapy.

Cell Death Dis 2018 01 18;9(2):23. Epub 2018 Jan 18.

UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.

Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCδ-selective activator, the 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCδ-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCδ-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCδ but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCδ-dependent manner. Additionally, the impairment of colonosphere growth and formation, associated with depletion of stemness markers, indicate that Roy-Bz also targets drug-resistant cancer stem cells, preventing tumor dissemination and recurrence. Notably, in xenograft mouse models, Roy-Bz showed a PKCδ-dependent antitumor effect, through anti-proliferative, pro-apoptotic, and anti-angiogenic activities. Besides, Roy-Bz was non-genotoxic, and in vivo it had no apparent toxic side effects. Collectively, our findings reveal a novel promising anticancer drug candidate. Most importantly, Roy-Bz opens the way to a new era on PKC biology and pharmacology, contributing to the potential redefinition of the structural requirements of isozyme-selective agents, and to the re-establishment of PKC isozymes as feasible therapeutic targets in human diseases.
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http://dx.doi.org/10.1038/s41419-017-0154-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833815PMC
January 2018