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1.
Nat Commun ; 12(1): 4118, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226542

RESUMO

Living cells actively migrate in their environment to perform key biological functions-from unicellular organisms looking for food to single cells such as fibroblasts, leukocytes or cancer cells that can shape, patrol or invade tissues. Cell migration results from complex intracellular processes that enable cell self-propulsion, and has been shown to also integrate various chemical or physical extracellular signals. While it is established that cells can modify their environment by depositing biochemical signals or mechanically remodelling the extracellular matrix, the impact of such self-induced environmental perturbations on cell trajectories at various scales remains unexplored. Here, we show that cells can retrieve their path: by confining motile cells on 1D and 2D micropatterned surfaces, we demonstrate that they leave long-lived physicochemical footprints along their way, which determine their future path. On this basis, we argue that cell trajectories belong to the general class of self-interacting random walks, and show that self-interactions can rule large scale exploration by inducing long-lived ageing, subdiffusion and anomalous first-passage statistics. Altogether, our joint experimental and theoretical approach points to a generic coupling between motile cells and their environment, which endows cells with a spatial memory of their path and can dramatically change their space exploration.


Assuntos
Movimento Celular/fisiologia , Memória Espacial/fisiologia , Células CACO-2 , Simulação por Computador , Matriz Extracelular/metabolismo , Fibroblastos , Humanos , Modelos Biológicos , RNA Interferente Pequeno
2.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199192

RESUMO

The beneficial effects of coffee on human diseases are well documented, but the molecular mechanisms of its bioactive compounds on cancer are not completely elucidated. This is likely due to the large heterogeneity of coffee preparations and different coffee-based beverages, but also to the choice of experimental models where proliferation, differentiation and immune responses are differently affected. The aim of the present study was to investigate the effects of one of the most interesting bioactive compounds in coffee, i.e., caffeine, using a cellular model of melanoma at a defined differentiation level. A preliminary in silico analysis carried out on public gene-expression databases identified genes potentially involved in caffeine's effects and suggested some specific molecular targets, including tyrosinase. Proliferation was investigated in vitro on human melanoma initiating cells (MICs) and cytokine expression was measured in conditioned media. Tyrosinase was revealed as a key player in caffeine's mechanisms of action, suggesting a crucial role in immunomodulation through the reduction in IL-1ß, IP-10, MIP-1α, MIP-1ß and RANTES secretion onto MICs conditioned media. The potent antiproliferative effects of caffeine on MICs are likely to occur by promoting melanin production and reducing inflammatory signals' secretion. These data suggest tyrosinase as a key player mediating the effects of caffeine on melanoma.


Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Simulação por Computador/estatística & dados numéricos , Melaninas/metabolismo , Melanoma/tratamento farmacológico , Monofenol Mono-Oxigenase/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Biologia Computacional/métodos , Bases de Dados Genéticas , Regulação da Expressão Gênica , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia
3.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199858

RESUMO

The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong treatment led to numerous severe side-effects (metabolic syndrome, hepatotoxicity, diabetes, etc.). The HIV-1 PRIs are capable of interacting with "secondary" targets (off-targets) characterized by different biological activities from that of HIV-1 protease. In this scenario, the in-silico techniques undoubtedly contributed to the design of new small molecules with well-fitting selectivity against the main target, analyzing possible undesirable interactions that are already in the early stages of the research process. The present work is focused on a new mixed-hierarchical, ligand-structure-based protocol, which is centered on an on/off-target approach, to identify the new selective inhibitors of HIV-1 PR. The use of the well-established, ligand-based tools available in the DRUDIT web platform, in combination with a conventional, structure-based molecular docking process, permitted to fast screen a large database of active molecules and to select a set of structure with optimal on/off-target profiles. Therefore, the method exposed herein, could represent a reliable help in the research of new selective targeted small molecules, permitting to design new agents without undesirable interactions.


Assuntos
Desenho de Fármacos , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacologia , Protease de HIV/química , HIV-1/efeitos dos fármacos , Domínio Catalítico , Simulação por Computador , Infecções por HIV/enzimologia , Infecções por HIV/virologia , HIV-1/enzimologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200392

RESUMO

Knowledge of all the intermolecular forces occurring in ionic liquids (ILs) is essential to master their properties. Aiming at investigating the weaker hydrogen bonding in aprotic liquids, the present work combined computational study and far-infrared spectroscopy on four imidazolium-based ILs with different anions. The DFT calculations of the ionic couples, using the ωB97X-D functional and considering both the empirical dispersion corrections and the presence of a polar solvent, show that, for all samples, the lowest energy configurations of the ion pair present H atoms, directly bound to C atoms of the cation and close to O atoms of the anion, capable of creating moderate to weak hydrogen bonding with anions. For the liquids containing anions of higher bonding ability, the absorption curves generated from the calculated vibrational frequencies and intensities show absorption bands between 100 and 125 cm-1 corresponding to the stretching of the hydrogen bond. These indications are in complete agreement with the presently reported temperature dependence of the far-infrared spectrum, where the stretching modes of the hydrogen bonding are detected only for samples presenting a moderate interaction and become particularly prominent at low temperatures. Moreover, from the analysis of the infrared spectra, the occurrence of various phase transitions as a function of temperature was detected, and the difference in the average energy between the H-bonded and the dispersion-governed molecular configurations was evaluated.


Assuntos
Simulação por Computador , Teoria da Densidade Funcional , Imidazóis/química , Líquidos Iônicos/química , Espectrofotometria Infravermelho/métodos , Ligação de Hidrogênio , Modelos Químicos
5.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201208

RESUMO

Tyrosinase is the central enzyme involved in the highly complex process of melanin formation, catalyzing the rate-limiting steps of this biosynthetic pathway. Due to such a preponderant role, it has become a major target in the treatment of undesired skin pigmentation conditions and also in the prevention of enzymatic food browning. Numerous phenolic-based structures from natural sources have been pointed out as potential tyrosinase inhibitors, including anthocyanins. The aim of the present study was to individually assess the tyrosinase inhibitory activity of eight purified compounds with a variable degree of structural complexity: native anthocyanins, deoxyanthocyanins, and pyranoanthocyanins. The latter two, the groups of anthocyanin-related compounds with enhanced stability, were tested for the first time. Compounds 1 to 4 (luteolinidin, deoxymalvidin, cyanidin-, and malvidin-3-O-glucoside) revealed to be the most effective inhibitors, and further kinetic studies suggested their inhibition mechanism to be of a competitive nature. Structure-activity relationships were proposed based on molecular docking studies conducted with mushroom tyrosinase (mTYR) and human tyrosinase-related protein 1 (hTYRP1) crystal structures, providing information about the binding affinity and the different types of interactions established with the enzyme's active center which corroborated the findings of the inhibition and kinetic studies. Overall, these results support the applicability of these compounds as pigmentation modulators.


Assuntos
Antocianinas/química , Antocianinas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Agaricales/enzimologia , Catálise , Simulação por Computador , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxirredução , Relação Estrutura-Atividade
6.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199598

RESUMO

In this work, we use the next sub-volume method (NSM) to investigate the possibility of using the compartment-based ("on-lattice") model to simulate water radiolysis. We, first, start with a brief description of the reaction-diffusion master equation (RDME) in a spatially discretized simulation volume ("mesh"), which is divided into sub-volumes (or "voxels"). We then discuss the choice of voxel size and merging technique of a given mesh, along with the evolution of the system using the hierarchical algorithm for the RDME ("hRDME"). Since the compartment-based model cannot describe high concentration species of early radiation-induced spurs, we propose a combination of the particle-based step-by-step ("SBS") Brownian dynamics model and the compartment-based model ("SBS-RDME model") for the simulation. We, finally, use the particle-based SBS Brownian dynamics model of Geant4-DNA as a reference to test the model implementation through several benchmarks. We find that the compartment-based model can efficiently simulate the system with a large number of species and for longer timescales, beyond the microsecond, with a reasonable computing time. Our aim in developing this model is to study the production and evolution of reactive oxygen species generated under irradiation with different dose rate conditions, such as in FLASH and conventional radiotherapy.


Assuntos
DNA/química , Transferência Linear de Energia , Modelos Moleculares , Água/química , Algoritmos , Simulação por Computador , Difusão , Modelos Químicos , Método de Monte Carlo , Radiólise de Impulso
7.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199659

RESUMO

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2-4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery.


Assuntos
DNA/efeitos dos fármacos , Quadruplex G/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/química , Telômero/química , Sítios de Ligação/efeitos dos fármacos , Dicroísmo Circular , Simulação por Computador , DNA/química , DNA/ultraestrutura , Humanos , Ligantes , Simulação de Dinâmica Molecular , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-myc/ultraestrutura , Telômero/efeitos dos fármacos , Telômero/genética
8.
Sensors (Basel) ; 21(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203160

RESUMO

Multi-UAV systems are attracting, especially in the last decade, the attention of researchers and companies of very different fields due to the great interest in developing systems capable of operating in a coordinated manner in complex scenarios and to cover and speed up applications that can be dangerous or tedious for people: search and rescue tasks, inspection of facilities, delivery of goods, surveillance, etc. Inspired by these needs, this work aims to design, implement and analyze a trajectory planning and collision avoidance strategy for multi-UAV systems in 3D environments. For this purpose, a study of the existing techniques for both problems is carried out and an innovative strategy based on Fast Marching Square-for the planning phase-and a simple priority-based speed control-as the method for conflict resolution-is proposed, together with prevention measures designed to try to limit and reduce the greatest number of conflicting situations that may occur between vehicles while they carry out their missions in a simulated 3D urban environment. The performance of the algorithm is evaluated successfully on the basis of certain conveniently chosen statistical measures that are collected throughout the simulation runs.


Assuntos
Algoritmos , Gestão de Riscos , Simulação por Computador , Humanos
9.
Sensors (Basel) ; 21(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203320

RESUMO

Ultrasound echoscopy technologies are continuously evolving towards new modalities including quantitative parameter imaging, elastography, 3D scanning, and others. The development and analysis of new methods and algorithms require an adequate digital simulation of radiofrequency (RF) signal transformations. The purpose of this paper is the quantitative evaluation of RF signal simulation uncertainties in resolution and contrast reproduction with the model of a phased array transducer. The method is based on three types of standard physical phantoms. Digital 3D models of those phantoms are composed of point scatterers representing the weak backscattering of the background material and stronger backscattering from inclusions. The simulation results of echoscopy with sector scanning transducer by Field II software are compared with the RF output of the Ultrasonix scanner after scanning standard phantoms with 2.5 MHz phased array. The quantitative comparison of axial, lateral, and elevation resolutions have shown uncertainties from 9 to 22% correspondingly. The echoscopy simulation with two densities of scatterers is compared with contrast phantom imaging on the backscattered RF signals and B-scan reconstructed image, showing that the main sources of uncertainties limiting the echoscopy RF signal simulation adequacy are an insufficient knowledge of the scanner and phantom's parameters. The attempt made for the quantitative evaluation of simulation uncertainties shows both problems and the potential of echoscopy simulation in imaging technology developments. The analysis presented could be interesting for researchers developing quantitative ultrasound imaging and elastography technologies looking for simulated raw RF signals comparable to those obtained from real ultrasonic scanning.


Assuntos
Algoritmos , Transdutores , Simulação por Computador , Imagens de Fantasmas , Ultrassonografia
10.
Sensors (Basel) ; 21(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203508

RESUMO

The influence of earthquake disasters on human social life is positively related to the magnitude and intensity of the earthquake, and effectively avoiding casualties and property losses can be attributed to the accurate prediction of earthquakes. In this study, an electromagnetic sensor is investigated to assess earthquakes in advance by collecting earthquake signals. At present, the mainstream earthquake magnitude prediction comprises two methods. On the one hand, most geophysicists or data analysis experts extract a series of basic features from earthquake precursor signals for seismic classification. On the other hand, the obtained data related to earth activities by seismograph or space satellite are directly used in classification networks. This article proposes a CNN and designs a 3D feature-map which can be used to solve the problem of earthquake magnitude classification by combining the advantages of shallow features and high-dimensional information. In addition, noise simulation technology and SMOTE oversampling technology are applied to overcome the problem of seismic data imbalance. The signals collected by electromagnetic sensors are used to evaluate the method proposed in this article. The results show that the method proposed in this paper can classify earthquake magnitudes well.


Assuntos
Aprendizado Profundo , Desastres , Terremotos , Simulação por Computador , Fenômenos Eletromagnéticos , Humanos
11.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206424

RESUMO

Determination of the metabolism pathway of xenobiotics undergoing the hepatic pass is a crucial aspect in drug development since the presence of toxic biotransformation products may result in significant side effects during the therapy. In this study, the complete hepatic metabolism pathway of dapoxetine established according to the human liver microsome assay with the use of a high-resolution LC-MS system was described. Eleven biotransformation products of dapoxetine, including eight metabolites not reported in the literature so far, were detected and identified. N-dealkylation, hydroxylation, N-oxidation and dearylation were found to be the main metabolic reactions for the investigated xenobiotic. In silico analysis of toxicity revealed that the reaction of didesmethylation may contribute to the increased carcinogenic potential of dapoxetine metabolites. On the other hand, N-oxidation and aromatic hydroxylation biotransformation reactions possibly lead to the formation of mutagenic compounds.


Assuntos
Benzilaminas , Simulação por Computador , Microssomos Hepáticos/química , Naftalenos , Benzilaminas/química , Benzilaminas/farmacocinética , Biotransformação , Cromatografia Líquida de Alta Pressão , Humanos , Naftalenos/química , Naftalenos/farmacocinética
12.
Sensors (Basel) ; 21(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206512

RESUMO

The 12-lead electrocardiogram was invented more than 100 years ago and is still used as an essential tool in the early detection of heart disease. By estimating the time-varying source of the electrical activity from the potential changes, several types of heart disease can be noninvasively identified. However, most previous studies are based on signal processing, and thus an approach that includes physics modeling would be helpful for source localization problems. This study proposes a localization method for cardiac sources by combining an electrical analysis with a volume conductor model of the human body as a forward problem and a sparse reconstruction method as an inverse problem. Our formulation estimates not only the current source location but also the current direction. For a 12-lead electrocardiogram system, a sensitivity analysis of the localization to cardiac volume, tilted angle, and model inhomogeneity was evaluated. Finally, the estimated source location is corrected by Kalman filter, considering the estimated electrocardiogram source as time-sequence data. For a high signal-to-noise ratio (greater than 20 dB), the dominant error sources were the model inhomogeneity, which is mainly attributable to the high conductivity of the blood in the heart. The average localization error of the electric dipole sources in the heart was 12.6 mm, which is comparable to that in previous studies, where a less detailed anatomical structure was considered. A time-series source localization with Kalman filtering indicated that source mislocalization could be compensated, suggesting the effectiveness of the source estimation using the current direction and location simultaneously. For the electrocardiogram R-wave, the mean distance error was reduced to less than 7.3 mm using the proposed method. Considering the physical properties of the human body with Kalman filtering enables highly accurate estimation of the cardiac electric signal source location and direction. This proposal is also applicable to electrode configuration, such as ECG sensing systems.


Assuntos
Algoritmos , Processamento de Sinais Assistido por Computador , Simulação por Computador , Eletrocardiografia , Humanos , Razão Sinal-Ruído
13.
Sensors (Basel) ; 21(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206620

RESUMO

We present a deep learning solution to the problem of localization of magnetoencephalography (MEG) brain signals. The proposed deep model architectures are tuned to single and multiple time point MEG data, and can estimate varying numbers of dipole sources. Results from simulated MEG data on the cortical surface of a real human subject demonstrated improvements against the popular RAP-MUSIC localization algorithm in specific scenarios with varying SNR levels, inter-source correlation values, and number of sources. Importantly, the deep learning models had robust performance to forward model errors resulting from head translation and rotation and a significant reduction in computation time, to a fraction of 1 ms, paving the way to real-time MEG source localization.


Assuntos
Aprendizado Profundo , Magnetoencefalografia , Algoritmos , Encéfalo , Mapeamento Encefálico , Simulação por Computador , Eletroencefalografia , Humanos , Modelos Neurológicos
14.
Sensors (Basel) ; 21(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209456

RESUMO

Monitoring of an underwater environment and communication is essential for many applications, such as sea habitat monitoring, offshore investigation and mineral exploration, but due to underwater current, low bandwidth, high water pressure, propagation delay and error probability, underwater communication is challenging. In this paper, we proposed a sensor node clustering technique for UWSNs named as adaptive node clustering technique (ANC-UWSNs). It uses a dragonfly optimization (DFO) algorithm for selecting ideal measure of clusters needed for routing. The DFO algorithm is inspired by the swarming behavior of dragons. The proposed methodology correlates with other algorithms, for example the ant colony optimizer (ACO), comprehensive learning particle swarm optimizer (CLPSO), gray wolf optimizer (GWO) and moth flame optimizer (MFO). Grid size, transmission range and nodes density are used in a performance matrix, which varies during simulation. Results show that DFO outperform the other algorithms. It produces a higher optimized number of clusters as compared to other algorithms and hence optimizes overall routing and increases the life span of a network.


Assuntos
Algoritmos , Tecnologia sem Fio , Análise por Conglomerados , Simulação por Computador , Sistemas Computacionais
15.
Sensors (Basel) ; 21(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209748

RESUMO

Cryosurgery is a technique of growing popularity involving tissue ablation under controlled freezing. Technological advancement of devices along with surgical technique improvements have turned cryosurgery from an experimental to an established option for treating several diseases. However, cryosurgery is still limited by inaccurate planning based primarily on 2D visualization of the patient's preoperative images. Several works have been aimed at modelling cryoablation through heat transfer simulations; however, most software applications do not meet some key requirements for clinical routine use, such as high computational speed and user-friendliness. This work aims to develop an intuitive platform for anatomical understanding and pre-operative planning by integrating the information content of radiological images and cryoprobe specifications either in a 3D virtual environment (desktop application) or in a hybrid simulator, which exploits the potential of the 3D printing and augmented reality functionalities of Microsoft HoloLens. The proposed platform was preliminarily validated for the retrospective planning/simulation of two surgical cases. Results suggest that the platform is easy and quick to learn and could be used in clinical practice to improve anatomical understanding, to make surgical planning easier than the traditional method, and to strengthen the memorization of surgical planning.


Assuntos
Realidade Aumentada , Criocirurgia , Simulação por Computador , Humanos , Estudos Retrospectivos , Software
16.
Sensors (Basel) ; 21(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209986

RESUMO

According to experts and medical literature, healthy thyroids and thyroids containing benign nodules tend to be less inflamed and less active than those with malignant nodules. It seems to be a consensus that malignant nodules have more blood veins and more blood circulation. This may be related to the maintenance of the nodule's heat at a higher level compared with neighboring tissues. If the internal heat modifies the skin radiation, then it could be detected by infrared sensors. The goal of this work is the investigation of the factors that allow this detection, and the possible relation with any pattern referent to nodule malignancy. We aim to consider a wide range of factors, so a great number of numerical simulations of the heat transfer in the region under analysis, based on the Finite Element method, are performed to study the influence of each nodule and patient characteristics on the infrared sensor acquisition. To do so, the protocol for infrared thyroid examination used in our university's hospital is simulated in the numerical study. This protocol presents two phases. In the first one, the body under observation is in steady state. In the second one, it is submitted to thermal stress (transient state). Both are simulated in order to verify if it is possible (by infrared sensors) to identify different behavior referent to malignant nodules. Moreover, when the simulation indicates possible important aspects, patients with and without similar characteristics are examined to confirm such influences. The results show that the tissues between skin and thyroid, as well as the nodule size, have an influence on superficial temperatures. Other thermal parameters of thyroid nodules show little influence on surface infrared emissions, for instance, those related to the vascularization of the nodule. All details of the physical parameters used in the simulations, characteristics of the real nodules and thermal examinations are publicly available, allowing these simulations to be compared with other types of heat transfer solutions and infrared examination protocols. Among the main contributions of this work, we highlight the simulation of the possible range of parameters, and definition of the simulation approach for mapping the used infrared protocol, promoting the investigation of a possible relation between the heat transfer process and the data obtained by infrared acquisitions.


Assuntos
Nódulo da Glândula Tireoide , Simulação por Computador , Humanos , Temperatura
17.
Chimia (Aarau) ; 75(6): 518-521, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34233816

RESUMO

Proteins with large and flat binding sites as well as protein-protein interactions are considered ' undruggable ' with conventional small-molecule drugs. Cyclic peptides have been found to be capable of binding to such targets with high affinity, making this class of compounds an interesting source for possible therapeutics. However, the oftentimes poor passive membrane permeability of cyclic peptides still imposes restrictions on the applicability of cyclic peptide drugs. Here, we describe how computational methods in combination with experimental data can be used to improve our understanding of the structure-permeability relationship. Especially the conformational dynamic and chameleonic nature of cyclic peptides, which we investigate by a combination of MD simulations and kinetic modeling, is important for their ability to permeate passively through the membrane. The insights from such studies may enable the formulation of design principles for the rational design of permeable cyclic peptides.


Assuntos
Peptídeos Cíclicos , Proteínas , Permeabilidade da Membrana Celular , Simulação por Computador , Peptídeos Cíclicos/metabolismo , Permeabilidade
18.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201401

RESUMO

The limited number of medicinal products available to treat of fungal infections makes control of fungal pathogens problematic, especially since the number of fungal resistance incidents increases. Given the high costs and slow development of new antifungal treatment options, repurposing of already known compounds is one of the proposed strategies. The objective of this study was to perform in vitro experimental tests of already identified lead compounds in our previous in silico drug repurposing study, which had been conducted on the known Drugbank database using a seven-step procedure which includes machine learning and molecular docking. This study identifies siramesine as a novel antifungal agent. This novel indication was confirmed through in vitro testing using several yeast species and one mold. The results showed susceptibility of Candida species to siramesine with MIC at concentration 12.5 µg/mL, whereas other candidates had no antifungal activity. Siramesine was also effective against in vitro biofilm formation and already formed biofilm was reduced following 24 h treatment with a MBEC range of 50-62.5 µg/mL. Siramesine is involved in modulation of ergosterol biosynthesis in vitro, which indicates it is a potential target for its antifungal activity. This implicates the possibility of siramesine repurposing, especially since there are already published data about nontoxicity. Following our in vitro results, we provide additional in depth in silico analysis of siramesine and compounds structurally similar to siramesine, providing an extended lead set for further preclinical and clinical investigation, which is needed to clearly define molecular targets and to elucidate its in vivo effectiveness as well.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Indóis/química , Indóis/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Simulação por Computador , Reposicionamento de Medicamentos/métodos , Ergosterol/metabolismo , Aprendizado de Máquina , Simulação de Acoplamento Molecular/métodos
19.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202844

RESUMO

The COVID-19 pandemic, as well as the more general global increase in viral diseases, has led researchers to look to the plant kingdom as a potential source for antiviral compounds. Since ancient times, herbal medicines have been extensively applied in the treatment and prevention of various infectious diseases in different traditional systems. The purpose of this review is to highlight the potential antiviral activity of plant compounds as effective and reliable agents against viral infections, especially by viruses from the coronavirus group. Various antiviral mechanisms shown by crude plant extracts and plant-derived bioactive compounds are discussed. The understanding of the action mechanisms of complex plant extract and isolated plant-derived compounds will help pave the way towards the combat of this life-threatening disease. Further, molecular docking studies, in silico analyses of extracted compounds, and future prospects are included. The in vitro production of antiviral chemical compounds from plants using molecular pharming is also considered. Notably, hairy root cultures represent a promising and sustainable way to obtain a range of biologically active compounds that may be applied in the development of novel antiviral agents.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Extratos Vegetais/farmacologia , Plantas Medicinais/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/imunologia , Antivirais/uso terapêutico , Simulação por Computador , Humanos , Agricultura Molecular/métodos , Extratos Vegetais/química , Extratos Vegetais/imunologia , Extratos Vegetais/uso terapêutico , Plantas Medicinais/imunologia , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos
20.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208139

RESUMO

Glioblastoma is the most malignant brain tumor among adults. Despite multimodality treatment, it remains incurable, mainly because of its extensive heterogeneity and infiltration in the brain parenchyma. Recent evidence indicates dysregulation of the expression of the Promyelocytic Leukemia Protein (PML) in primary Glioblastoma samples. PML is implicated in various ways in cancer biology. In the brain, PML participates in the physiological migration of the neural progenitor cells, which have been hypothesized to serve as the cell of origin of Glioblastoma. The role of PML in Glioblastoma progression has recently gained attention due to its controversial effects in overall Glioblastoma evolution. In this work, we studied the role of PML in Glioblastoma pathophysiology using the U87MG cell line. We genetically modified the cells to conditionally overexpress the PML isoform IV and we focused on its dual role in tumor growth and invasive capacity. Furthermore, we targeted a PML action mediator, the Enhancer of Zeste Homolog 2 (EZH2), via the inhibitory drug DZNeP. We present a combined in vitro-in silico approach, that utilizes both 2D and 3D cultures and cancer-predictive computational algorithms, in order to differentiate and interpret the observed biological results. Our overall findings indicate that PML regulates growth and invasion through distinct cellular mechanisms. In particular, PML overexpression suppresses cell proliferation, while it maintains the invasive capacity of the U87MG Glioblastoma cells and, upon inhibition of the PML-EZH2 pathway, the invasion is drastically eliminated. Our in silico simulations suggest that the underlying mechanism of PML-driven Glioblastoma physiology regulates invasion by differential modulation of the cell-to-cell adhesive and diffusive capacity of the cells. Elucidating further the role of PML in Glioblastoma biology could set PML as a potential molecular biomarker of the tumor progression and its mediated pathway as a therapeutic target, aiming at inhibiting cell growth and potentially clonal evolution regarding their proliferative and/or invasive phenotype within the heterogeneous tumor mass.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteína da Leucemia Promielocítica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Humanos , Modelos Biológicos , Invasividade Neoplásica , Esferoides Celulares/patologia
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