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1.
Sports (Basel) ; 12(7)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39058072

RESUMO

(1) Background: Adolescents who are under the care of child and youth institutions are vulnerable due to factors that can include disruption to family structure or education and adverse experiences. They often experience poor or unstable support systems, leaving them at risk of delinquency. In this context, sports engagement may provide a stable structure and have positive effects in this population. Therefore, the purpose of this study was to explore the perceptions, knowledge, beliefs, and behaviors regarding social and emotional skills among at-risk adolescents, with a specific focus on their engagement in sports. (2) Methods: Ninety-six adolescents aged 12 to 17 years (66 female, 30 male), residing in child and youth care institutions across Italy, Portugal, the UK, and Turkey, participated in this study. The participants were divided into 14 focus groups, each with six to eight participants of similar ages. (3) Results: Thematic analysis revealed four main themes: Emotional causes of behavioral problems; Emotional skills to regain control; Social support makes sports worthwhile; Sport as a socio-emotional resource. (4) Conclusions: The study findings highlight that although sports create many challenging emotional situations for these adolescents, they also provides resources that may help them cope with their emotions within and beyond sports.

2.
Pharmaceutics ; 16(7)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39065561

RESUMO

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via Toll-like receptors 7/8 when formulated in carriers, like nanogels, for topical use. An effective alternative to conventional therapies is the nanoparticle drug delivery system. We studied lipidic nanoparticles with IQ (Lipo IQ) and functionalized them with a DNA aptamer, AT11 (Lipo IQ AT11), to improve the selectivity for cervical cancer cells combined with the efficacy of essential oils. The formulations showed that the physicochemical properties are adequate for vaginal drug delivery and have antimicrobial activity at higher concentrations (with MIC50 starting from 0.625%). The final formulations exhibited cytotoxicity in cancer cells, enhanced by essential oils without affecting healthy cells, resulting in less than 10% cell viability in HeLa cells and over 60% in NHDF cells. Essential oils potentiate Lipo IQ's effectiveness, while AT11 increases the selectivity for cervical cancer cells. As suggested by the results of the permeation assay, the formulations were internalized by the cancer cells. Overall, the obtained results suggested that the synergistic effect of the essential oils and the nanosystem potentiate the cytotoxic effect of Lipo IQ and that Lipo IQ AT11 promotes selectivity towards cancer cells.

3.
Crit Rev Food Sci Nutr ; : 1-9, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38950579

RESUMO

Bioactive peptides from brewer's spent grain (BSG) and brewer's spent yeast (BSY), two by-products of the brewing industry, have great potential as functional food ingredients, dietary supplements or nutraceuticals to reduce the risk of numerous pathological conditions. Nevertheless, the oral administration of these peptides poses great challenges since peptides must undergo gastrointestinal digestion, intestinal absorption and hepatic metabolism, which can affect their bioavailability and, therefore, the expected outcomes. This review provides a comprehensive and critical analysis of the potential impact of the oral route on the bioactivity of BSG/BSY peptides as assessed by in vitro assays and identifies research gaps that require novel approaches/methodologies. The data collected indicate that in addition to the significant influence of gastrointestinal digestion, intestinal absorption and hepatic metabolism also have a major impact on the bioactivity of brewing peptides. The major gap identified was the insufficient evidence regarding hepatic metabolism, which points for the need of employing in vitro assays in this research field to provide such clarification. Thus, to reach the market, the impact of the oral route on the bioactivities of BSG/BSY peptides must be properly studied in vitro to allow adequate/effective administration (dosage/frequency) with a beneficial impact on the population health.

4.
BMC Geriatr ; 24(1): 557, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38918696

RESUMO

BACKGROUND: Polypharmacy in older adults with cancer receiving chemotherapy leads to increased risks of drug interactions, translating in potential hazardous health outcomes. This study aims to assess the prevalence of polypharmacy, drug-drug interactions (DDIs), and severe-drug interactions (SDIs) in older patients with cancer. Antineoplastic agents (ANAs) involvement and possible risk contexts (comorbidities with cardiac risk, and high-risk medications) were also analysed. METHODS: Observational study with older adults (≥ 65 years) diagnosed with cancer, who were treated with antineoplastic agents (ANAs); it was conducted in three hospitals from the north of Portugal. Data collection was obtained using self-reports and medical records. DDIs were identified and classified using Micromedex® software. Descriptive and association analyze statistics were performed. Statistical hypothesis tests with p value less than 0.05 were considered significant. All statistical procedures and analysis were performed with R version 4.1.3. RESULTS: We enrolled 552 patients. Polypharmacy prevalence was 88.40%; 76.45% and 56.16% of the patients presented with DDIs and SDIs, respectively. SDIs with ANAs were found in 21.20% of the patients. High-risk medications were associated with a higher risk of polypharmacy, DDIs, and SDIs. Polypharmacy and DDIs were higher in patients with hypertension or diabetes. SDIs were higher in patients with diabetes. CONCLUSION: Polypharmacy, potential DDIs and SDIs were highly prevalent in older adults with cancer. A careful review of the medication administered is necessary to decrease it. These findings warrant further research to optimize medication in this population and decrease problems related to medication, which may lead to emergency room visits and hospitalisations, compromising patient safety and/or ongoing treatments.


Assuntos
Antineoplásicos , Interações Medicamentosas , Neoplasias , Polimedicação , Humanos , Interações Medicamentosas/fisiologia , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Masculino , Feminino , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Idoso de 80 Anos ou mais , Fatores de Risco , Portugal/epidemiologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-38717706

RESUMO

Phytol is a diterpene constituent of many essential oils, belonging to the group of unsaturated acyclic alcohols. Although phytol possesses antimycobacterial and anti-inflammatory effects, no reports of a gastrointestinal action are available from the literature. Due to the well-known shortcomings of classical anti-ulcer drugs (e.g. side effects or relapses), natural products may offer an attractive alternative. In this study, a potential gastroprotective activity of phytol was evaluated using acute and chronic ulcer models in rats. Phytol 12.5, 25 and 50 mg/kg, administered orally 1 h prior to induction of gastric lesions by absolute ethanol, inhibited the lesion area by 96, 90 and 95%, respectively. When lesions were induced by ischemia and reperfusion, phytol 12.5 and 25 mg/kg per os decreased the lesion areas by 89 and 46%, respectively. In the third acute ulcer model (lesions induced by ibuprofen), phytol 12.5 mg/kg reduced the lesion area by 55%. Phytol restored the decreased level of reduced glutathione, the increased levels of myeloperoxidase and malondialdehyde and the decreased levels of catalase and superoxide dismutase in rats with gastric ulcer induced by ethanol to levels obtained in vehicle group. Finally, in a chronic model in which gastric ulcer was induced by acetic acid directly instilled into the stomach, phytol administered orally over a time period of 7 days at 12.5, 25, 50 and 100 mg/kg reduced lesion areas by 84, 81, 83 and 68%. Our data suggest a gastroprotective and cicatrizing effect of phytol, possibly associated with its antioxidant effect.

6.
Cureus ; 16(3): e55978, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38618380

RESUMO

Dermatomyositis (DM) is an inflammatory myopathy often paraneoplastic in nature. Patients have characteristic cutaneous findings and possible muscle involvement. In the latter, muscle enzymes are elevated, and the electromyogram shows varied changes. Muscle or skin biopsy and myositis-specific antibodies confirm the diagnosis. Here, we report the case of an 86-year-old woman with cutaneous lesions, proximal weakness, and sicca symptoms. Muscle enzymes and electromyogram were normal. Antinuclear antibodies were elevated, and anti-TIF1γ and anti-Ro52 antibodies were positive. Muscle biopsy was compatible with the diagnosis of DM, and salivary gland biopsy confirmed Sjögren's syndrome. Malignancy investigation identified a rectal cancer, which was resected. This case illustrates a rare form of cancer presentation - anti-TIF1γ DM with normal muscle enzymes and electromyogram and concomitant secondary Sjögren's syndrome. Malignancy screening and multidisciplinary management were crucial to a successful approach.

7.
Cureus ; 16(2): e54933, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38544612

RESUMO

Airway complications account for a significant amount of post-thyroidectomy complications. Forgotten goiter is a residual thyroid mass left after total thyroidectomy, an event already depicted in the literature. Clinical presentation is diverse, ranging from asymptomatic tracheal deviation to symptoms caused by hormonally active thyroid tissue or airway obstruction due to mass effect. However, it has never been documented as the cause of acute respiratory distress following thyroid surgery. We report the case of a 65-year-old female undergoing left hemithyroidectomy due to long-standing substernal goiter. Anesthesia induction and surgery were uneventful. On extubation, the patient presented with acute respiratory distress requiring prompt airway management. A computed tomography scan revealed residual intrathoracic goiter resulting in significant airway compression. Therefore, although a rare event, a forgotten goiter should be considered by a multidisciplinary team when patients undergoing surgery for substernal goiter develop acute postoperative airway obstruction after common post-thyroidectomy complications have been excluded.

8.
Nutrients ; 16(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474865

RESUMO

Obesity entails metabolic alterations across multiple organs, highlighting the role of inter-organ communication in its pathogenesis. Extracellular vesicles (EVs) are communication agents in physiological and pathological conditions, and although they have been associated with obesity comorbidities, their protein cargo in this context remains largely unknown. To decipher the messages encapsulated in EVs, we isolated plasma-derived EVs from a diet-induced obese murine model. Obese plasma EVs exhibited a decline in protein diversity while control EVs revealed significant enrichment in protein-folding functions, highlighting the importance of proper folding in maintaining metabolic homeostasis. Previously, we revealed that gut-derived EVs' proteome holds particular significance in obesity. Here, we compared plasma and gut EVs and identified four proteins exclusively present in the control state of both EVs, revealing the potential for a non-invasive assessment of gut health by analyzing blood-derived EVs. Given the relevance of post-translational modifications (PTMs), we observed a shift in chromatin-related proteins from glycation to acetylation in obese gut EVs, suggesting a regulatory mechanism targeting DNA transcription during obesity. This study provides valuable insights into novel roles of EVs and protein PTMs in the intricate mechanisms underlying obesity, shedding light on potential biomarkers and pathways for future research.


Assuntos
Vesículas Extracelulares , Proteômica , Humanos , Camundongos , Animais , Obesidade/metabolismo , Processamento de Proteína Pós-Traducional , Proteoma/metabolismo , Vesículas Extracelulares/metabolismo
9.
J Invasive Cardiol ; 36(3)2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38441988

RESUMO

OBJECTIVES: Coronary angiography (CAG)-derived physiology methods have been developed in an attempt to simplify and increase the usage of coronary physiology, based mostly on dynamic fluid computational algorithms. We aimed to develop a different approach based on artificial intelligence methods, which has seldom been explored. METHODS: Consecutive patients undergoing invasive instantaneous free-wave ratio (iFR) measurements were included. We developed artificial intelligence (AI) models capable of classifying target lesions as positive (iFR ≤ 0.89) or negative (iFR > 0.89). The predictions were then compared to the true measurements. RESULTS: Two hundred-fifty measurements were included, and 3 models were developed. Model 3 had the best overall performance: accuracy, negative predictive value (NPV), positive predictive value (PPV), sensitivity, and specificity were 69%, 88%, 44%, 74%, and 67%, respectively. Performance differed per target vessel. For the left anterior descending artery (LAD), model 3 had the highest accuracy (66%), while model 2 the highest NPV (86%) and sensitivity (91%). PPV was always low/modest. Model 1 had the highest specificity (68%). For the right coronary artery, model 1's accuracy was 86%, NPV was 97%, and specificity was 87%, but all models had low PPV (maximum 25%) and low/modest sensitivity (maximum 60%). For the circumflex, model 1 performed best: accuracy, NPV, PPV, sensitivity, and specificity were 69%, 96%, 24%, 80%, and 68%, respectively. CONCLUSIONS: We developed 3 AI models capable of binary iFR estimation from CAG images. Despite modest accuracy, the consistently high NPV is of potential clinical significance, as it would enable avoiding further invasive maneuvers after CAG. This pivotal study offers proof of concept for further development.


Assuntos
Inteligência Artificial , Aprendizado Profundo , Humanos , Projetos Piloto , Raios X , Angiografia Coronária
10.
Fitoterapia ; 175: 105861, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38354824

RESUMO

Humulus lupulus extracts have in their composition different molecules, such as polyphenols, α-acids, ß-acids, and hydrocarbons, which contribute to the plant's medicinal properties. These molecules are associated with antimicrobial, antioxidant and anti-inflammatory activities. OBJECTIVE: This work focuses on the evaluation of H. lupulus biological activities, with the aim of evaluating its potential for inclusion in cosmetic formulations. METHODS: Two distinct aqueous extracts and two hydrolates obtained via hydrodistillation were evaluated. These include the flower parts (FE, FH) and the mix of aboveground parts (ME, MH). The chemical profiles for both aqueous extracts and hydrolates were identified by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). Antimicrobial, antioxidant, cytotoxicity, and anti-inflammatory activity were tested in vitro using standard methods. RESULTS: Rutin was the major compound found in FE (40.041 µg mg-1 of extract) and ME (2.909 µg mg-1 of extract), while humulenol II was the most abundant compound in hydrolates (FH: 20.83%; MH: 46.80%). Furthermore, FE was able to inhibit the growth of Staphylococcus aureus and Staphylococcus epidermis with MIC values of 50% and 25% (v/v), respectively. FH showed the same effect in Staphylococcus aureus (50% v/v). FH evidenced poor antioxidant potential in DPPH scavenging test and demonstrated significant antioxidant and anti-inflammatory effects by reducing (***p < 0.001) intracellular reactive oxygen species (ROS), NO (nitric oxide) levels (***p < 0.001) and cyclooxygenase-2 (COX-2) protein expression (***p < 0.001) in lipopolysaccharide (LPS)-stimulated macrophages. Nevertheless, it is important to note that FH exhibited cytotoxicity at high concentrations in 3T3 fibroblasts and RAW 264.7 macrophages. CONCLUSION: The studied H. lupulus aqueous extracts and hydrolates revealed that FH stands out as the most promising bioactive source for cosmetic formulations. However, future research addressing antimicrobial activity is necessary to confirm its potential incorporation into dermatological and cosmetic formulations.


Assuntos
Anti-Inflamatórios , Antioxidantes , Cosméticos , Humulus , Extratos Vegetais , Humulus/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , Camundongos , Animais , Células RAW 264.7 , Flores/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Macrófagos/efeitos dos fármacos , Testes de Sensibilidade Microbiana
11.
Pharmacy (Basel) ; 12(1)2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38392925

RESUMO

Observational, cross-sectional prevalence studies are costly and time-consuming. The development of indirect methods estimating prevalence used to obtain faster, less-expensive, and more robust results would be an advantage for several healthcare applications. This study aimed to use the drug dispensing data from community pharmacies to estimate the prevalence of Type 2 Diabetes mellitus (T2DM) in the Portuguese population. A cross-sectional study was conducted using a database of dispensed medicines with an indication for Diabetes mellitus in 2018 and 2021, stratified by geographic region. The methodology was based on a sequential method of acquiring prevalence estimates obtained through exposure to medicines using the daily doses defined per thousand inhabitants per day and adjusted to the rate of adherence to therapy, prescription patterns, and concomitance of antidiabetic drugs. The estimated overall T2DM prevalence in 2018 was 13.9%, and it was 14.2% for 2021. The results show the increased consumption of antidiabetic drugs, with fixed-dose combination antidiabetics and new antidiabetics being particularly important in 2021. This work allowed for the development of a model to obtain the estimated prevalence of T2DM based on drug consumption, using a simple, fast, and robust method that is in line with the available evidence. However, with the recent expanding indications for new antidiabetics, the inclusion of further data in the model needs to be studied.

13.
Molecules ; 28(23)2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-38067447

RESUMO

Quercetin (QUE) is the most widely used flavonoid for therapeutic purposes. To improve the available knowledge about the properties of some natural products, determining the amount of QUE is crucial. The main objective of this systematic review is to identify the analytical methods validated for detecting and quantifying QUE in different matrices and characterize their sensitivity. A search was conducted until 30 June 2023 in the PubMed database for experimental studies that addressed the validation of chromatographic analytical methods to detect and quantify QUE from consumable natural products. Only studies published between 2018 and 2022, written in English, were included. The risk of bias was assessed by emphasizing methods of comparison according to previously published studies. Descriptive statistics were used to depict the obtained results. The studies were analyzed based on the type of QUE source, chromatographic method, and validation parameters. A total of 17 studies were included in this review. Plants were the most commonly analyzed source of QUE. Among the detection methods, spectrophotometry proved to be the most widely used, surpassing mass spectrometry (MS). After analyzing the bias, all the included studies mentioned/presented, totally or partially, at least four of the eight parameters.


Assuntos
Produtos Biológicos , Quercetina , Quercetina/química , Flavonoides/química , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas
14.
Pharmaceuticals (Basel) ; 16(12)2023 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-38139862

RESUMO

The evaluation of the efficacy of incorporation of quercetin in nanoparticles is crucial, both for the development and quality control of pharmaceutical formulations. The validation of analytical methods for the precise quantification of quercetin is useful for the evaluation of various potential quercetin delivery systems and quercetin pharmacokinetics. This work aimed to validate a high-performance liquid chromatography with diode array detection (HPLC-DAD) method for quercetin detection and quantification in nanoparticles. Different mobile phase conditions and detection wavelengths (254 and 368 nm) were tested, and the major validation parameters were assessed (precision, accuracy, linearity, sensitivity, stability, and selectivity). The best peak resolution was obtained when quercetin was analyzed at 368 nm with a mobile phase of 1.5% acetic acid and a water/acetonitrile/methanol ratio of 55:40:5. Under these conditions, quercetin also eluted rapidly (retention time of 3.6 min). The method proved to be linear (R2 > 0.995), specific, and repeatable (variation coefficient between 2.4% and 6.7%) and presented intermediate precision (variation coefficient between 7.2% and 9.4%). The accuracy of the analysis ranged between 88.6% and 110.7%, and detection and quantification limits were 0.046 and 0.14 µg/mL, respectively. Quercetin solutions were more stable when stored at 4 °C than at room temperature or -20 °C. This validated method satisfied more parameters of bias assessment than most recent methods for quercetin determination and presented itself as more sensitive and efficient than general spectrophotometric methods. The method was successfully used for the analysis of quercetin incorporation in nanoparticles and will be evaluated in the future for its adequacy for the determination of quercetin in more complex matrices.

16.
Nat Microbiol ; 8(11): 2033-2049, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37845315

RESUMO

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.


Assuntos
Encefalopatia Hepática , Lactulose , Humanos , Camundongos , Animais , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/prevenção & controle , Antibacterianos/uso terapêutico
17.
Expert Opin Ther Targets ; 27(11): 1043-1058, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37789645

RESUMO

INTRODUCTION: Ubiquitin-specific protease 7 (USP7) also known as herpesvirus-associated ubiquitin-specific protease (HAUSP) is a well-characterized cysteine protease that belongs to the largest subfamily of deubiquitinating enzymes (DUBs). It is involved in multiple signaling pathways, some of them dysregulated in malignant tumors. USP7 inhibition can lead to cell growth arrest and apoptosis through inhibition of tumor promoters and stabilization of tumor suppressors, making it a promising druggable target for cancer therapy. AREAS COVERED: This review covers the structure of USP7, its function in multiple signaling pathways and relevance in cancer, as well as recent advances and future perspectives in the development of USP7 inhibitors for cancer therapy. EXPERT OPINION: Literature reports display the multiple antitumor activities of USP7 inhibitors, both in vitro and in vivo. Nonetheless, none have entered clinical trials so far, highlighting the need to delve into a deeper understanding of USP7 binding sites and the development of more accurate compound screening methods. Despite these challenges, further development of USP7 inhibitors is promising as a valuable new approach for cancer treatment, including the ability to address chemoresistance.


Assuntos
Neoplasias , Humanos , Peptidase 7 Específica de Ubiquitina/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Sítios de Ligação , Ubiquitina Tiolesterase/metabolismo , Linhagem Celular Tumoral
18.
J Clin Med ; 12(20)2023 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-37892584

RESUMO

Head and neck free-flap microvascular surgeries are complex and resource-intensive procedures where proper conduct of anaesthesia plays a crucial role in the outcome. Flap failure and postoperative complications can be attributed to multiple factors, whether surgical- or anaesthesia-related. The anesthesiologist should ensure optimised physiological conditions to guarantee the survival of the flap and simultaneously decrease perioperative morbidity. Institutions employ different anaesthetic techniques and results vary across centres. In our institution, two different total intravenous approaches have been in use: a remifentanil-based approach and a multimodal opioid-sparing approach, which is further divided into an opioid-free anaesthesia (OFA) subgroup. We studied every consecutive case performed between 2015 and 2022, including 107 patients. Our results show a significant reduction in overall complications (53.3 vs. 78.9%, p = 0.012), length of stay in the intensive care unit (3.43 ± 5.51 vs. 5.16 ± 4.23 days, p = 0.046), duration of postoperative mechanical ventilation (67 ± 107 vs. 9 ± 38 h, p = 0.029), and the need for postoperative vasopressors (10% vs. 46.6%, p = 0.001) in the OFA group (vs. all other patients). The multimodal and OFA strategies have multiple differences regarding the fluid therapy, intraoperative type of vasopressor used, perioperative pathways, and various drug choices compared to the opioid-based technique. Due to the small number of cases in our study, we could not isolate any attitude, as an independent factor, from the success of the OFA strategy as a whole. Large randomised controlled trials are needed to improve knowledge and help define the ideal anaesthetic management of these patients.

19.
J Comput Aided Mol Des ; 37(12): 791-806, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37847342

RESUMO

In this work, we develop a method for generating targeted hit compounds by applying deep reinforcement learning and attention mechanisms to predict binding affinity against a biological target while considering stereochemical information. The novelty of this work is a deep model Predictor that can establish the relationship between chemical structures and their corresponding [Formula: see text] values. We thoroughly study the effect of different molecular descriptors such as ECFP4, ECFP6, SMILES and RDKFingerprint. Also, we demonstrated the importance of attention mechanisms to capture long-range dependencies in molecular sequences. Due to the importance of stereochemical information for the binding mechanism, this information was employed both in the prediction and generation processes. To identify the most promising hits, we apply the self-adaptive multi-objective optimization strategy. Moreover, to ensure the existence of stereochemical information, we consider all the possible enumerated stereoisomers to provide the most appropriate 3D structures. We evaluated this approach against the Ubiquitin-Specific Protease 7 (USP7) by generating putative inhibitors for this target. The predictor with SMILES notations as descriptor plus bidirectional recurrent neural network using attention mechanism has the best performance. Additionally, our methodology identify the regions of the generated molecules that are important for the interaction with the receptor's active site. Also, the obtained results demonstrate that it is possible to discover synthesizable molecules with high biological affinity for the target, containing the indication of their optimal stereochemical conformation.


Assuntos
Inteligência Artificial , Desenho de Fármacos , Redes Neurais de Computação , Estrutura Molecular
20.
Microorganisms ; 11(10)2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37894056

RESUMO

The role of the fungal community, the mycobiota, in the health of the vagina is currently an important area of research. The emergence of new sequencing technologies and advances in bioinformatics made possible the discovery of novel fungi inhabiting this niche. Candida spp. constitutes the most important group of opportunistic pathogenic fungi, being the most prevalent fungal species in vulvovaginal infections. However, fungi such as Rhodotorula spp., Naganishia spp. and Malassezia spp. have emerged as potential pathogens in this niche, and therefore it is clinically relevant to understand their ecological interaction with Candida spp. The main aim of this study was to evaluate the impact of yeasts on Candida albicans' pathogenicity, focusing on in-vitro growth, and biofilm formation at different times of co-culture and germ tube formation. The assays were performed with isolated species or with co-cultures of C. albicans (ATCC10231) with one other yeast species: Rhodotorula mucilaginosa (DSM13621), Malassezia furfur (DSM6170) or Naganishia albida (DSM70215). The results showed that M. furfur creates a symbiotic relationship with C. albicans, enhancing the growth rate of the co-culture (149.69%), and of germ tube formation of C. albicans (119.8%) and inducing a higher amount of biofilm biomass of the co-culture, both when mixed (154.1%) and preformed (166.8%). As for the yeasts R. mucilaginosa and N. albida, the relationship is antagonistic (with a significant decrease in all assays), thus possibly repressing the mixture's pathogenicity. These results shed light on the complex interactions between yeasts in the vaginal mycobiome.

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