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- Chronotherapy of Brain Diseases: Assessment of the Circadian Rhythms of Efflux Transporters at the Blood-cerebrospinal Fluid BarrierPublication . Furtado, André Filipe Lino ; Paixão, Telma Alexandra Quintela; Santos, Cecília Reis Alves; Gallardo Alba, Maria EugéniaThe choroid plexus (CP) is an integral part of the blood cerebrospinal-fluid barrier (BCSFB). The CP is formed by a monolayer of cuboidal epithelial cells united by tight junctions. On the apical side, these cells present microvilli and are in contact with the cerebrospinal fluid (CSF). On the basal membrane, these cells are surrounded by a vast network of capillary blood vessels. The CP is responsible for several functions that are vital to the homeostasis of the central nervous system (CNS) where we include the production of the CSF, synthesis of several proteins, CNS protection against foreign elements, CSF detoxification from noxious compounds that result from normal cell metabolism and the transport of multiple molecules across the BCSFB. The CP has an essential role on the transport across the BCSFB of therapeutic molecules targeting the CNS. For that, it expresses multiple membrane transporters that have been described in the literature as essential for the transport of therapeutic compounds across CNS biological barriers. Recently, a functional molecular clock was described in the CP. This means that the biological functions of this structure might have a circadian rhythmicity associated. There's the possibility that this circadian clock influences membrane transporters' expression and activity at the CP which would result in circadian changes of the bioavailability of therapeutic compounds in the CNS depending on the time of administration. As such, the main goal of this doctoral thesis was to analyse the influence of circadian rhythms on the expression of multiple membrane transporters on the CP. Additionally, we used therapeutic compounds, namely methotrexate (MTX) and donepezil (DNPZ) to assess the relation between the CP's membrane transporters circadian expression and their drug transport function across the BCSFB. One of the objectives of this project, as mentioned earlier, was to assess the circadian expression of multiple CP’s membrane transporters. For that, CP primary cell cultures of neonate rats were used. We concluded that rSlc9a1 and rSlc1a5 expression was rhythmic during a 24-hour period while rSlc47a1 did not reveal a circadian pattern. This work also aimed at disclosing the influence of sex on the daily expression oscillations of several ABC and SLC membrane transporters expressed by the CP. For this we used CPs from male, female, ovariectomized and sham-operated female rats. The results showed that the membrane transporter rAbcc1 is expressed in a circadian manner in the CP of male rats, while rAbcg2 presented circadian rhythmic expression in the CP of female rats. Both rAbcc4 and rOat3 were rhythmically expressed in the CP of male and female rats. Next, we used an in vitro model of the CP in order to evaluate the relevance of Abcc4’s circadian expression in the transport of MTX across the BCSFB. We demonstrated that MTX transport across the BCSFB was rhythmic. Besides, we also concluded that Abcc4 circadian expression might influence the MTX circadian transport across the BCSFB. Finally, this project also aimed to describe the impact of circadian rhythms on CP Abcg2 expression and also on the circadian transport profile of DNPZ across the BCSFB. Using CP primary cell cultures of neonate rats, we demonstrated the presence of rAbcg2 circadian expression. Next, using primary cell cultures, an in vitro model of the BCSFB was established and we discovered that DNPZ transport across the BCSFB presents circadian rhythmicity. Furthermore, it was also proposed that besides rABCG2, SLC22A4 could also be involved in the DNPZ circadian transport across the BCSFB. The results obtained in this project demonstrate that membrane transporters present circadian expression in the BCSFB. Moreover, the transport of therapeutic compounds, such as MTX and DNPZ, across the BCSFB is also influenced by the circadian rhythm of CP membrane transporters. In the future, it is essential to further exploit the role of circadian rhythms on the expression of membrane transporters at the CP and its influence on the transport of therapeutic compounds across the BCSFB. This information might prove vital in the treatment of CNS diseases. By timing drug administration with the period when they are more prone to reach the target tissue at the CNS, we are ensuring their maximum target tissue concentration, and a reduction in side effects.
- Fatores de risco genético para adenomas hipofisários: Uma análise nacional, multicêntrica, genética e clínicaPublication . Gaspar, Leonor Isabel Mesquita ; Lemos, Manuel Carlos Loureiro de; Gonçalves, Catarina Inês Nunes PiresOs adenomas hipofisários representam, aproximadamente, 10-15% do total dos tumores intracranianos. A prevalência destes tumores foi estimada em 1:1000 na população geral, sendo mais frequentemente diagnosticados entre os 40-60 anos de idade. Estes tumores são monoclonais, tipicamente benignos e de crescimento lento, no entanto podem estar associados a um aumento da morbilidade e mortalidade através da sobreprodução hormonal e dos efeitos de massa resultantes da compressão das estruturas adjacentes ao tumor. Os tumores hipofisários mais frequentes são os prolactinomas, seguido pelos adenomas hipofisários não funcionantes. Os mecanismos subjacentes à tumorigénese hipofisária não são ainda totalmente conhecidos, pelo que uma melhor compreensão desta questão ajudará a gerir a doença. O aumento do risco associado a mutações em genes como o AIP, MEN1, CDKN1B e PRKAR1A, fornece evidências de uma predisposição genética para adenomas hipofisários familiares. A grande maioria dos adenomas hipofisários (cerca de 95%) ocorre num contexto esporádico e na ausência de predisposição genética conhecida. No entanto, três polimorfismos (rs2359536, rs10763170 e rs17083838) foram significativamente associados a adenomas hipofisários esporádicos na população Chinesa Han. O objetivo geral desta tese foi realizar um estudo de âmbito multicêntrico nacional, acerca dos fatores de risco genético para o desenvolvimento de adenomas hipofisários familiares e esporádicos, de forma a ampliar o conhecimento sobre a tumorigénese hipofisária. Numa primeira fase desta tese, foi construída uma base de dados com todas as variantes germinativas identificadas no gene AIP publicadas em casos esporádicos e familiares de adenomas hipofisários, até à data, a nível mundial. Nesta revisão, foram identificadas e avaliadas, ao nível da sua patogenicidade, um total de 158 mutações germinativas entre 562 doentes com adenomas hipofisários esporádicos ou familiares. Estas variantes estavam localizadas em toda a região codificadora e nas regiões de splicing do gene AIP. A patogenicidade de todas as variantes germinativas publicadas foi categorizada de acordo com os critérios da American College of Medical Genetic and Genomics (ACMG), utilizando todos os dados disponíveis. Do número total de doentes, 35,4% apresentavam variantes patogénicas e 24,0% apresentavam variantes provavelmente patogénicas. Na segunda fase desta tese foi determinada a frequência de mutações germinativas do gene AIP em doentes portugueses com macroadenomas hipofisários esporádicos de início precoce. Para isso, foi sequenciado o gene AIP em 218 doentes com macroadenomas hipofisários esporádicos diagnosticados antes dos 40 anos. Foram identificadas variantes raras em heterozigotia neste gene em 18 (8,3%) doentes. No entanto, apenas quatro (1,8%) doentes apresentavam variantes patogénicas. Estas variantes compreendiam duas mutações já conhecidas (p.Arg81* e p.Leu115Trpfs*41) e duas mutações novas (p.Ser53Thrfs*36, e p.Glu246*). Estes quatro doentes tinham sido diagnosticados com somatotrofinoma em idades compreendidas entre os 14 e os 25 anos. A frequência de variantes patogénicas no gene AIP em doentes com idade inferior a 30 anos foi de 3,4% e com idade inferior a 18 anos foi de 5%, respetivamente. A frequência de mutações no gene AIP nesta coorte de doentes portugueses foi inferior à de outros estudos. A identificação de novas variantes no gene AIP expande o espetro das causas genéticas dos adenomas hipofisários e pode ajudar a compreender o papel das mutações neste gene nos mecanismos moleculares subjacentes à tumorigénese hipofisária. A terceira fase desta tese consistiu em identificar mutações germinativas num conjunto específico de 29 genes, descritos na literatura como tendo mutações germinativas em doentes com adenomas hipofisários, numa coorte de doentes portugueses diagnosticados com adenomas hipofisários esporádicos de início precoce. Para isso, foi feita a sequenciação completa do exoma em 225 doentes com macroadenomas hipofisários esporádicos diagnosticados até aos 40 anos de idade. Foram identificadas 154 variantes raras em 25 dos 29 genes. Destas foram identificadas três variantes patogénicas e 13 variantes provavelmente patogénicas, nos genes AIP, CDH23, MEN1, MSH2, PMS2, SDHB, TP53 e VHL, em 7,1% dos doentes. Nos doentes diagnosticados com idades inferiores a 30 e 18 anos, a frequência de mutações foi de 9,0% e 12%, respectivamente. Esta é, até à data, a maior análise multigénica de doentes com macroadenomas hipofisários esporádicos de início jovem. Confirmámos que o AIP é o gene mais frequentemente envolvido, mas também descobrimos causas genéticas mais raras de adenomas hipofisários, incluindo a primeira confirmação independente de um papel do gene CDH23. Na última fase desta tese foi avaliada a associação de três polimorfismos comuns próximos dos genes NEBL (rs2359536), PCDH15 (rs10763170) e CDK8 (rs17083838) à suscetibilidade a adenomas hipofisários esporádicos na população portuguesa. Foram determinadas as frequências genotípicas e alélicas de 570 casos e 546 controlos. O alelo minor CDK8 rs17083838 (alelo A) foi significativamente associado a adenomas hipofisários esporádicos. As variantes NEBL rs2359536 e PCDH15 rs10763170 não foram associadas a risco geral para a doença, embora tenha sido observada uma associação significativa entre o alelo minor PCDH15 rs10763170 (alelo T) e somatotrofinomas. Estes resultados sugerem que a variante CDK8 rs17083838, e possivelmente a variante PCDH15 rs10763170, podem aumentar a suscetibilidade a adenomas hipofisários esporádicos na população portuguesa. Concluindo, diferentes estratégias foram desenvolvidas e implementadas, ao longo desta tese, de forma a determinar quais os fatores de risco genético mais associados ao desenvolvimento de adenomas hipofisários esporádicos e familiares. Estes resultados são importantes sob o ponto de vista científico não só para uma melhor compreensão do panorama genético dos adenomas hipofisários, como também abrem portas para novas estratégias de rastreio genético direcionadas, oferecendo conhecimentos fundamentais para a gestão personalizada dos macroadenomas hipofisários de início precoce.
- Identificação de causas genéticas do hipogonadismo hipogonadotrófico congénito utilizando a sequenciação de nova geraçãoPublication . Carriço, Josianne Nunes; Lemos, Manuel Carlos Loureiro de; Gonçalves, Catarina Inês Nunes PiresO desenvolvimento pubertário é um processo fisiológico complexo que resulta da interação entre o sistema neuroendócrino, fatores genéticos e ambientais. Inicia-se com a reativação do eixo Hipotálamo-Hipófise-Gónadas, levando à produção de gonadotrofinas, hormonas sexuais e consequente desenvolvimento dos carateres sexuais secundários. O Hipogonadismo Hipogonadotrófico Congénito (HHC) é uma doença endócrina rara que, na adolescência, se manifesta clinicamente com ausência completa ou parcial do desenvolvimento dos caracteres sexuais secundários. Na idade adulta, os sintomas incluem ausência de virilização e disfunção erétil no sexo masculino, amenorreia primária no sexo feminino, ausência de líbido e infertilidade em ambos os sexos. O HHC caracteriza-se pela ausência ou diminuição da produção, secreção ou ação da hormona libertadora de gonadotrofinas. Em 50 a 60% dos casos associa-se a anosmia/hiposmia (Síndrome de Kallmann) ou a outras anomalias congénitas. O diagnóstico do HHC baseia-se na anamnese, observação de sinais clínicos, levantamento de sintomas e exames laboratoriais e imagiológicos. Contudo, desde o início do século XXI, o conhecimento sobre as causas genéticas do HHC tem avançado na mesma medida que o desenvolvimento das tecnologias de sequenciação genética. A disponibilidade das tecnologias de sequenciação de nova geração (NGS) proporcionou grandes avanços no diagnóstico molecular destes doentes. Este estudo teve como objetivo investigar as causas genéticas do HHC em doentes portugueses, utilizando a NGS, ferramentas in silico e técnicas de biologia molecular. Foram estudados 81 doentes com HHC e 263 controlos portugueses. O ADN genómico foi extraído dos leucócitos do sangue periférico e submetido à sequenciação do exoma completo. A partir das bases de dados OMIM® e Pubmed, identificaram-se 169 genes relacionados com o fenótipo de HHC, que foram incluídos num painel virtual. As variantes encontradas nesses genes foram filtradas com base na frequência populacional e localização no genoma, sendo classificadas conforme os critérios do American college of medical genetics and genomics e da Association for molecular pathology (ACMG-AMP) em cinco níveis, de benignas a patogénicas. Para avaliar o impacto de variantes com potencial para alterar o splicing, utilizou-se o método de minigene. A análise das variantes germinativas permitiu identificar a causa genética do HHC em 24 dos 81 doentes estudados (29,6%). As variantes causais estavam distribuídas por 10 dos 169 genes presentes no painel genético virtual analisado. Os genes GNRHR, FGFR1, ANOS1 e CHD7 foram os mais frequentemente afetados. Notavelmente, a ampliação do painel genético não resultou num aumentou considerável da taxa de diagnóstico. No entanto, é importante destacar que este estudo expandiu o espectro mutacional da doença, identificando várias variantes até então nunca descritas. A maioria das variantes encontradas foi classificada como de significado indeterminado (VUS), mas a taxa de VUS não diferiu significativamente entre doentes e controlos, com exceção do gene EGF, onde foram encontradas VUS exclusivamente nos doentes. Concluímos que a maioria dessas variantes raras não estão diretamente relacionadas com o fenótipo estudado, refletindo provavelmente o fundo genético da população portuguesa. Em relação à oligogenia, observou-se uma frequência de 6,2% entre os doentes (5/81), um valor estatisticamente mais elevado quando comparado com os controlos. O estudo funcional de uma variante identificada no gene CHD7 (NM_017780.4: c.4354G>T, p.Val1452Leu), resultou no aumento da taxa de diagnóstico para 30,9%, demonstrando a importância dos estudos funcionais na reclassificação de VUS. Este trabalho enfatizou a complexidade genética do HHC, reforçando a importância de uma compreensão aprofundada da doença, seja para estabelecer o diagnóstico e/ou o prognóstico, para ajudar no aconselhamento genético e tratamento, seja para o esclarecimento dos processos biológicos, que potencialmente poderão contribuir para o desenvolvimento de terapias dirigidas no futuro.
- Sweet Cherries as Health Promoters: Valuable Red Fruits with Nutritive and Functional PropertiesPublication . Gonçalves, Ana Carolina Almeida ; Silva, Luís Manuel Lopes Rodrigues da; Alves, Gilberto Lourenço; Ferreira, Amílcar Celta Falcão RamosCurrently, it is widely recognized that consuming fruits and vegetables effectively reduces the risk of morbidity and mortality caused by cardiovascular and cancerous diseases, among others, being widely recommended a daily intake of 400 g of fruits and vegetables. In fact, the potential of fruits and vegetables to treat various ailments and alleviate symptoms, such as migraines, metabolic syndrome, intestinal problems, physical pain, certain cancer types, rheumatoid arthritis, dizziness, colds, fever, psychological fatigue, and symptoms derived from rheumatoid arthritis, among others, has been known since ancient times. Nowadays, the trend is increasing, being accompanied by an emphasis on different communities. This interest is essentially since it is believed that, unlike synthetic pharmaceutics that cause undesirable side effects, natural products have few, or no side effects, and are easy to obtain and economical. Natural products have been the subject of many studies and an important topic of discussion among the medical and scientific communities. Indeed, the biological potential of a wide range of products has already been recognized, being already incorporated in many pharmaceutical drugs. These beneficial activities are directly related to their nutritional constituents, namely due to the presence of vitamins, minerals, carotenoids and fiber, as well as phenolic compounds. The combination of all these compounds is beneficial and capable of promoting the good functioning of human organisms, and hence, promoting the normalization of several parameters to basal levels and contributing to general well-being. Among the various compounds, special emphasis has been given to phenolic compounds. As far as we know, phenolic compounds derive from the secondary metabolism of plants and their main function is to protect them against abiotic (water, sunlight, and temperature) and biotic (attacks by microorganisms) factors. These are commonly divided into 2 large subclasses: (i) non-coloured phenolic compounds (e.g., hydroxybenzoic and hydroxycinnamic acids, flavan-3-ols, flavonols, among others) and (ii) coloured compounds (anthocyanins, which are largely responsible by the colors exhibited by various natural products). Recent research has demonstrated that their chemical structure gives them a remarkable ability to reduce levels of oxidative stress and interact with proinflammatory cascades, thus restoring basal levels and consequently reducing the risk of occurrence of many diseases, or alleviating your symptoms, and consequently, contributing to a better quality of life. The human body naturally possesses intracellular antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase) that are considered essential for the survival and health of the population, once, under physiological conditions, they are capable of balancing the levels of free radicals. However, given genetic factors, unexpected decompensation, severe discomfort, and lifestyle choices, such as sedentary habits, consumption of alcohol and tobacco, and/or intake of foods very rich in fats and calories, the aforementioned enzymes become insufficient to guarantee basal levels, leading to proteins, organs and cells injury. This damage is caused by high levels of free radicals and the appearance of exacerbated inflammatory responses in the human body. Consequently, this decompensation “triggers” for the appearance and progression of many diseases whose prevalence is increasing worldwide. These data are corroborated by many studies, which describe that free radicals and pro-inflammatory species are largely related to oxidative stress, and the appearance of various types of cancer, autoimmune diseases, such as rheumatoid arthritis, and syndromes, including the metabolic one. Given the mentioned facts, it is not surprising that many studies involving cherries consumption are being carried out, since it is urgent to find accessible and effective therapies for the entire population, and preferably natural based, in order to improve their quality of life. Cherry (Prunus avium Linnaeus) is a fruit highly appreciated by consumers, not only due to its organoleptic characteristics, but also due to its nutritional value and health benefits. In fact, it has been shown that this fruit is an excellent source of macro and micronutrients, and phytochemicals. In fact, this last class of compounds has been the subject of many studies, being a topic of discussion among various communities given their various positive effects on health. Among the different nutritional classes found, cherries have high contents of phenolic compounds, highlighting the presence, until now, of anthocyanins, flavan-3-ols, flavonols and hydroxycinnamic acids. Particularly, the main compounds identified are cyanidin 3-O-rutinoside and -glucoside, quercetin, rutin, kaempferol, catechin, and ρcoumaroylquinic and chlorogenic acids. Therefore, the richness of cherries in bioactive compounds has been one of the reasons for the growing interest of the scientific community in exploring the beneficial healthpromoting effects associated with their intake. Furthermore, consumers are increasingly well-informed and, once, they are looking for healthy products, such as cherries, there is verified an increase in their demand. Faced with this, the market responds by increasing their global production, especially of the cultivars that most attract consumers. To date, several scientific studies carried out on animals and humans suggest that consuming cherries reduces the risk of several inflammatory and chronic diseases, such as rheumatoid arthritis, cardiovascular diseases, diabetes and cancer. Clinical evidence has already demonstrated that consuming cherries can reduce the scale of pain caused by arthritis, gout and inflammation, possibly due to their ability to increase superoxide dismutase levels, and reduce inflammatory mediators (TNF-α, MDA and PGE-2) and serum levels of C-reactive protein levels, as well as inhibiting cyclooxygenase (COX)-2, which is one of the main proteins responsible for enhancing the pro-inflammatory response. Furthermore, cherries have also shown to be effective in reducing muscle pain, accelerating recovery and improving the performance of recreational exercisers and high-competition athletes, diminishing risk factors associated with the onset of diabetes and cardiovascular diseases, and associated with stress and anxiety, thus improving sleep and mood, memory and cognitive functions. More recently, it has been reported that the consumption of cherries can also alleviate hepatic steatosis and inhibit the activity of the α-glucosidase enzyme, thus delaying the conversion of starch and disaccharides into glucose. Furthermore, cherries also show potential to protect human erythrocytes against free radicals and to inhibit the proliferation of cancer cells. These health-promoting activities are closely related to cherry phenolic content, which is the main responsible for offering this berry, notable antioxidant and antiinflammatory capabilities. This fact is supported by several studies and correlations already performed. In recent years, the production of this fruit has increased considerably worldwide, including in Portugal. Our country produces around 20,000 tonnes per year. A large part of this production occurs in the Fundão region, and hence, it is not surprising that sweet cherries present a distinguished economic impact in this region. The availability of detailed information about their health-promoting properties could lead to an increase in consumer demand, raising their consumption and use of pharmaceutical and nutraceutical products, contributing to the valorisation of the region and the fixation of people and industrial companies. Therefore, with this doctoral project, the aim was to extensively characterize, for the first time, the quality parameters and phytochemical and mineral composition of the best-known cultivars in the region, with the intention of helping in the selection of the most promising cultivars. In total, 23 cultivars were characterized. The results obtained revealed that, among the cultivars studied, there are significant differences in the physicochemical characteristics and in the phenolic, mineral and volatile profiles, showing the verified variability between the various cherry cultivars is mainly influenced by the genotype of the cultivar. In general, Black star and Starkrimson cultivars had the highest soluble solids content, while the highest acidity value was found in Sweetheart cultivar. On the other hand, Cristalina, Kordia and Santina cultivars were those that exhibited the most intense/dark color, while the lightest ones were Sunburst and Sweetheart. Relatively to phenolic compounds, 46 phenolic compounds were identified by HPLC-DAD-ESI/MSn, including 9 hydroxycinnamic acids, 2 hydroxybenzoic acids, 13 flavonols, 5 flavan-3-ols, 2 flavanones, 1 flavanonol and 4 anthocyanins. Among the compounds, chlorogenic acids were the majority noncoloured phenolic compounds, while cyanidin 3-O-rutinoside was the most predominant coloured phenolic compound. Regarding their levels, Sunburst cultivar had the highest amounts of unstained compounds, while the Tavora, Garnet and 4-84 cultivars had the highest concentration of anthocyanins. With regard to mineral content, 27 were identified by ICP-MS and flame atomic absorption spectrometry, namely 12 essential and 15 non-essential. The element potassium (K) was the most abundant element detected in all cultivars, while Thallium (Tl) was the least abundant. On the other hand, the analysis of volatile organic compounds by SPME/GC-MS showed that cherries have a wide variety of these, having been detected a total of 66 volatiles from 8 different families, including 16 aldehydes, 23 alcohols, 6 ketones, 6 esters, 8 monoterpenes, 3 norisoprenoids, 2 hydrocarbons and 2 acids. Among the compounds, benzaldehyde, hexanal, nonanal, benzyl alcohol, (E)-2-hexen-1-ol, 1- hexanol, (Z)-2-hexen -1-ol, 2-ethyl-1-hexanol, linalool, α-terpineol and α-ionone were the main found. Based on the obtained results, from a commercial point of view, Cristalina, Saco, Tavora, 4-84, Bigalise, Celeste and Satin cultivars might be considered some of the most interesting cultivars, since they offer a better flavor and a higher percentage of edible fruit, and consequently, major intake of phytochemicals, mainly due to their size, weight, and phenolic, mineral and volatile contents. The microbial ecology of the Saco cultivar was also explored for the first time. In total, 22 different bacteria and 33 fungi were isolated. The genera of Pseudomonas spp. (27.273%) and Ralstonia spp. (18.182%) were the most dominant bacteria, followed by Bacillus spp., Staphylococcus spp., Erwinia spp., Tatumella spp. and Dermacoccus spp. (each with 9.091%). Regarding fungi, Metschnikowia spp. (39.394%) was the most abundant genus, followed by Aureobasidium spp. (27.273%) and Hanseniaspora spp. (18.182%). In the initial stages of fruit development, Erwinia Tasmaniensis, Peudomonas viridiflava and Pseudomonas syringae bacteria are the first to emerge, while Ralstonia pickettii, Bacillus altitudinis, Enterococcus Rotai, Tatumellla terrea, Pseudomonas qingdaonensis, Pseudomonas gramininis, Dermacoccus nishinomiyaensis and Buttiauxella ferragutiae appear in the final stages of fruit ripening. Regarding fungi, Metschnikowia spp. (39.39%) was the most abundant genus, followed by Aureobasidium spp. (27.27%) and Hanseniaspora spp. (18.18%). The majority of fungi were detected in the final stages of fruit ripening, particularly the fungi Hanseniaspora uvarum, Metschnikowia pulcherrima, Hanseniaspora pseudoguilliermondii, Penicillium crustosum, Hanseniaspora meyeri, Aureobasidium proteae and Aureobasidium pullulans. The study of the microbial ecology of fruits and vegetables is vital because they can be a potential vector of foodborne pathogenic diseases and/or an important reservoir of microorganisms capable of improving the quality, characteristics and nutritional value of foods, and exert positive effects on human health. The isolation of certain microorganisms can also be an added value at an industrial level. Additionally, the in vitro biological properties of Saco cultivar were also evaluated, namely its potential to reduce free radicals and pro-inflammatory levels, as well as its potential to protect human blood samples against hemolysis and hemoglobin oxidation, interfere with the growth of cancer cells and with the activity of P-glycoprotein (P-gp), one of the main proteins related to resistance seen against several drugs, as well of αglucosidase enzyme. It was also observed that both fractions and the total extract can also inhibit the activity of α-glucosidase enzyme. Saco cultivar was chosen to carry out these assays, since it already showed to possess considerable biological properties and also for being one of the most produced cultivars in Portugal, possessing inclusive, protected geographical indication. Therefore, with the intention of increasing knowledge of the biological potential of the various phenolic compounds, and for the first time, 2 fractions rich in phenolic compounds were extracted using a solid phase C18 column, a fraction I, rich in noncoloured phenolic compounds, and fraction II, rich in anthocyanins. For comparison purposes, a total extract (III) rich in both phenolic subclasses was also tested and the results were further compared between them and with positive controls. In general, the three extracts showed a remarkable ability to capture free radicals and ferric species, as well as to interfere with the activity of proteins related to inflammation (iNOS and COX-2), and with the transmembrane transport protein, P-gp, as well as with the activity of α-glucosidase enzyme, in dose-dependent manner. It was also possible to verify that the three extracts demonstrated effectiveness in inhibiting the proliferation of cancer cells, namely colon, stomach and liver cancer cells, causing necrosis at the highest concentration (800 µg/mL for colon and stomach cells) and 100 µg/mL for liver cells). Both fractions and the total extract also showed the ability to reduce induced-oxidative stress in cancer cells, as well as in neuroblastoma model cells. From the obtained data, it is important to highlight the biological potential of the fraction rich in anthocyanins, which is in accordance with the literature. In fact, anthocyanins have been a target of many studies, due to their chemical structure. Indeed, anthocyanins are composed of several hydroxyl groups, which gives them a remarkable biological potential, namely, to reduce levels of free radicals and inflammation. Furthermore, it was also verified that the interaction between different phenolic compounds, which was observed in the total extract, was an added value in the majority of the assays done. In order to deepen the results obtained, the antioxidant activity of the main individual phenolic compounds present in cherries was evaluated against DPPH, nitric oxide and superoxide radicals. The obtained values for the DPPH radical revealed that anthocyanins, (-)-epicatechin and kaempferol 3-O-rutinoside were the most active phenolic compounds against this radical, while isorhamnetin 3-O-glucoside was the least. On the other hand, anthocyanins, (-)-epicatechin, quercetin 3-O-glucoside and caffeic acid proved to be the most effective in scavenging nitric oxide radicals, while ρhydroxybenzoic acid was the least efficient. In relation to the superoxide radical, quercetin and its derivatives showed the highest capacity, while cyanidin aglycone did not show the potential to intercept this radical at the concentrations tested. Additionally, molecular docking and absorption, distribution, metabolism, and excretion (ADME) studies were carried out, and it was observed that compounds with lower molecular masses, such as kaempferol, can easily interact with proteins related to oxidative stress, interfering in their activity, and thus, contributing to lower the concentration of free radicals to basal levels. The results obtained are highly promising and encourage translation into clinical trials, as well as the incorporation of cherries and/or their extracts into new medicines, cosmetic products, food supplements and nutraceuticals.