Prediction of permeability across intestinal cell monolayers for 219 disparate chemicals using in vitro experimental coefficients in a pH gradient system and in silico analyses by trivariate linear regressions and machine learning

2021 ◽  
pp. 114749
Author(s):  
Yusuke Kamiya ◽  
Asuka Omura ◽  
Riku Hayasaka ◽  
Rie Saito ◽  
Izumi Sano ◽  
...  
Keyword(s):  
Machine Learning ◽  
In Silico ◽  
Ph Gradient ◽  
Intestinal Cell ◽  
Gradient System ◽  
Cell Monolayers ◽  
In Silico Analyses ◽  
Linear Regressions

scholarly journals Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2505
Author(s):  
Raheem Remtulla ◽  
Sanjoy Kumar Das ◽  
Leonard A. Levin
Keyword(s):  
Machine Learning ◽  
Neural Networks ◽  
In Silico ◽  
Disulfide Bonds ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

scholarly journals Comparative In Vitro and In Silico Analyses of Variants in Splicing Regions of BRCA1 and BRCA2 Genes and Characterization of Novel Pathogenic Mutations

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e57173 ◽  
Author(s):  
Mara Colombo ◽  
Giovanna De Vecchi ◽  
Laura Caleca ◽  
Claudia Foglia ◽  
Carla B. Ripamonti ◽  
...  
Keyword(s):  
In Silico ◽  
Brca1 And Brca2 ◽  
Pathogenic Mutations ◽  
Brca1 And Brca2 Genes ◽  
In Silico Analyses

scholarly journals β-Cyclodextrin Does not Alter the Bioaccessibility and the Uptake by Caco-2 Cells of Olive By-Product Phenolic Compounds

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1653 ◽  
Author(s):  
Aurélia Malapert ◽  
Valérie Tomao ◽  
Marielle Margier ◽  
Marion Nowicki ◽  
Béatrice Gleize ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
In Vitro Digestion ◽  
Intestinal Cell ◽  
Coumaric Acid ◽  
Two Phase ◽  
Cell Monolayers ◽  
Vegetation Water ◽  
And Storage ◽  
Olive Mill

Alperujo—a two-phase olive mill waste that is composed of olive vegetation water and solid skin, pulp, and seed fragments - is a highly valuable olive by-product due to its high content in phenolic compounds. In this study, we assessed whether β-cyclodextrin (β-CD), which is used to extract and protect alpejuro phenolic compounds (hydroxytyrosol-O-glucoside, tyrosol, caffeic, and p-coumaric acids) could impact on their bioaccessibility (i.e., the percentage of molecule found in the aqueous phase of the digesta) and uptake by intestinal cells, by using an in vitro digestion model and Caco-2 TC7 cells in culture, respectively. Our results showed that β-CD did not change the bioaccessibility of the selected phenols. Hydroxytyrosol-O-glucoside and caffeic did not cross Caco-2 cell monolayers. Conversely ferulic acid, identified as the main caffeic acid intestinal metabolite, was absorbed through intestinal cell monolayers (~20%). Interestingly, β-CD moderately but significantly improved the local absorption of tyrosol and p-coumaric acid (2.3 + 1.4% and 8.5 ± 4.2%, respectively, p < 0.05), even if their final bioavailability (expressed as bioaccessibility × absorption by Caco-2 cells) was not modified (16.2 ± 0.6% vs. 16.8 ± 0.5% for tyrosol and 32.0 ± 3.2% vs. 37.2 ± 3.2% for p-coumaric acid, from pure alperujo and alperujo complexed with β-CD, respectively). Overall, our results show that β-CD is an interesting extraction and storage agent for phenolic compounds that does not alter their in vitro bioavailability.

Bufadienolides from Kalanchoe daigremontiana modulate the enzymatic activity of plasmin - In vitro and in silico analyses

2018 ◽  
Vol 120 ◽  
pp. 1591-1600 ◽  
Author(s):  
Joanna Kolodziejczyk-Czepas ◽  
Bartłomiej Pasiński ◽  
Michal B. Ponczek ◽  
Barbara Moniuszko-Szajwaj ◽  
Mariusz Kowalczyk ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
In Silico ◽  
In Silico Analyses ◽  
Kalanchoë Daigremontiana ◽  
Kalanchoe Daigremontiana

scholarly journals An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin

Biology ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 264
Author(s):  
Marta Calvo Tardón ◽  
Eliana Marinari ◽  
Denis Migliorini ◽  
Viviane Bes ◽  
Stoyan Tankov ◽  
...  
Keyword(s):  
Cell Lines ◽  
In Silico ◽  
Chemotherapy Resistance ◽  
Viable Cell ◽  
Gene Signature ◽  
Cell Number ◽  
Viable Cell Number ◽  
In Silico Analyses

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, characterized by a high degree of intertumoral heterogeneity. However, a common feature of the GBM microenvironment is hypoxia, which can promote radio- and chemotherapy resistance, immunosuppression, angiogenesis, and stemness. We experimentally defined common GBM adaptations to physiologically relevant oxygen gradients, and we assessed their modulation by the metabolic drug metformin. We directly exposed human GBM cell lines to hypoxia (1% O2) and to physioxia (5% O2). We then performed transcriptional profiling and compared our in vitro findings to predicted hypoxic areas in vivo using in silico analyses. We observed a heterogenous hypoxia response, but also a common gene signature that was induced by a physiologically relevant change in oxygenation from 5% O2 to 1% O2. In silico analyses showed that this hypoxia signature was highly correlated with a perinecrotic localization in GBM tumors, expression of certain glycolytic and immune-related genes, and poor prognosis of GBM patients. Metformin treatment of GBM cell lines under hypoxia and physioxia reduced viable cell number, oxygen consumption rate, and partially reversed the hypoxia gene signature, supporting further exploration of targeting tumor metabolism as a treatment component for hypoxic GBM.

Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions

2020 ◽  
Vol 319 (2) ◽  
pp. L360-L368
Author(s):  
Perwez Alam ◽  
Garima Agarwal ◽  
Rahul Kumar ◽  
Aastha Mishra ◽  
Neeru Saini ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
High Altitude ◽  
In Silico ◽  
Hypobaric Hypoxia ◽  
Umbilical Vein ◽  
Direct Interaction ◽  
Vascular Homeostasis ◽  
High Altitude Pulmonary Edema ◽  
In Silico Analyses

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.

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