scholarly journals Partial Least Square Model (PLS) as a Tool to Predict the Diffusion of Steroids Across Artificial Membranes

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1387
Author(s):  
Eleni Tsanaktsidou ◽  
Christina Karavasili ◽  
Constantinos K. Zacharis ◽  
Dimitrios G. Fatouros ◽  
Catherine K. Markopoulou
Keyword(s):  
Animal Experiments ◽  
Pharmaceutical Research ◽  
Partial Least Square ◽  
Least Square ◽  
Predictive Tool ◽  
Apparent Permeability ◽  
Internal Validation ◽  
Candidate Drug ◽  
Apparent Permeability Coefficient

One of the most challenging goals in modern pharmaceutical research is to develop models that can predict drugs’ behavior, particularly permeability in human tissues. Since the permeability is closely related to the molecular properties, numerous characteristics are necessary in order to develop a reliable predictive tool. The present study attempts to decode the permeability by correlating the apparent permeability coefficient (Papp) of 33 steroids with their properties (physicochemical and structural). The Papp of the molecules was determined by in vitro experiments and the results were plotted as Y variable on a Partial Least Squares (PLS) model, while 37 pharmacokinetic and structural properties were used as X descriptors. The developed model was subjected to internal validation and it tends to be robust with good predictive potential (R2Y = 0.902, RMSEE = 0.00265379, Q2Y = 0.722, RMSEP = 0.0077). Based on the results specific properties (logS, logP, logD, PSA and VDss) were proved to be more important than others in terms of drugs Papp. The models can be utilized to predict the permeability of a new candidate drug avoiding needless animal experiments, as well as time and material consuming experiments.

scholarly journals Global metabolomic and lipidomic analysis reveals the potential mechanisms of hemolysis effect of Ophiopogonin D and Ophiopogonin D' in vivo

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Huan-Hua Xu ◽  
Zhen-Hong Jiang ◽  
Cong-Shu Huang ◽  
Yu-Ting Sun ◽  
Long-Long Xu ◽  
...  
Keyword(s):  
Chemical Properties ◽  
Principal Component ◽  
Partial Least Square ◽  
Least Square ◽  
Practical Significance ◽  
Plasma Metabolites ◽  
Active Components ◽  
The Difference

Abstract Background OPD and OPD' are the two main active components of Ophiopogon japonicas in Shenmai injection (SMI). Being isomers of each other, they are supposed to have similar pharmacological activities, but the actual situation is complicated. The difference of hemolytic behavior between OPD and OPD' in vivo and in vitro was discovered and reported by our group for the first time. In vitro, only OPD' showed hemolysis reaction, while in vivo, both OPD and OPD' caused hemolysis. In vitro, the primary cause of hemolysis has been confirmed to be related to the difference between physical and chemical properties of OPD and OPD'. In vivo, although there is a possible explanation for this phenomenon, the one is that OPD is bio-transformed into OPD' or its analogues in vivo, the other one is that both OPD and OPD' were metabolized into more activated forms for hemolysis. However, the mechanism of hemolysis in vivo is still unclear, especially the existing literature are still difficult to explain why OPD shows the inconsistent hemolysis behavior in vivo and in vitro. Therefore, the study of hemolysis of OPD and OPD' in vivo is of great practical significance in response to the increase of adverse events of SMI. Methods Aiming at the hemolysis in vivo, this manuscript adopted untargeted metabolomics and lipidomics technology to preliminarily explore the changes of plasma metabolites and lipids of OPD- and OPD'-treated rats. Metabolomics and lipidomics analyses were performed on ultra-high performance liquid chromatography (UPLC) system tandem with different mass spectrometers (MS) and different columns respectively. Multivariate statistical approaches such as principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA) were applied to screen the differential metabolites and lipids. Results Both OPD and OPD' groups experienced hemolysis, Changes in endogenous differential metabolites and differential lipids, enrichment of differential metabolic pathways, and correlation analysis of differential metabolites and lipids all indicated that the causes of hemolysis by OPD and OPD' were closely related to the interference of phospholipid metabolism. Conclusions This study provided a comprehensive description of metabolomics and lipidomics changes between OPD- and OPD'-treated rats, it would add to the knowledge base of the field, which also provided scientific guidance for the subsequent mechanism research. However, the underlying mechanism require further research.

Bicarbonate secretion in rat distal colon in vitro: a measurement technique

1988 ◽  
Vol 254 (3) ◽  
pp. C383-C390 ◽  
Author(s):  
G. M. Feldman ◽  
S. F. Berman ◽  
R. L. Stephenson
Keyword(s):  
Short Circuit ◽  
Distal Colon ◽  
Apparent Permeability ◽  
Chemical Gradients ◽  
Acid Generation ◽  
Rat Distal Colon ◽  
Tissue Surfaces ◽  
Apparent Permeability Coefficient ◽  
Transepithelial Voltage

To study HCO3- secretion in rat distal colon, we utilized a technique that permits control of electrical and chemical transepithelial gradients. With symmetrical solutions (pH 7.4, [HCO3-] 25 mM, and CO2 tension 40 mmHg) bathing both tissue surfaces and under short-circuit conditions, HCO3- secretion remained stable for greater than 4 h at 1 mueq. h-1.cm-2. As the mucosal solution was alkalinized, the serosal solution was acidified at 3.1 mueq.h-1.cm-2. Ninety-four percent of serosal acidification was accounted for by the rate of metabolic lactic acid generation and transepithelial HCO3- secretion. Clamping transepithelial voltage reversibly affected net HCO3- secretion, and a linear relationship existed between clamped mucosal voltage and net HCO3- flux (r = 0.99); mucosal voltage of -68 mV completely inhibited net secretion. The apparent permeability coefficient of the colon to HCO3- is 2.8 X 10(-6) cm/s. One millimolar ouabain completely inhibited net HCO3- secretion. Acetazolamide (10(-4) M) inhibited secretion by approximately 50%, whereas a 10(-3) M concentration inhibited secretion by 90%. These data demonstrate that net colonic HCO3- secretion can be measured without imposed electrical and chemical gradients and that this flux is voltage sensitive and depends on carbonic anhydrase and Na+-K+-ATPase activities.

scholarly journals Multivariate Statistical Analysis Uncovers Spectrum–Effect Relationship between HPLC Fingerprints and Antioxidant Activity of Saffron

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Ya You ◽  
Zijin Xu ◽  
Qingrou Zhong ◽  
Lin Zhu ◽  
Susu Lin ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Quality Control ◽  
Evaluation Method ◽  
Control Method ◽  
Partial Least Square ◽  
Least Square ◽  
Crocus Sativus ◽  
Effect Relationship ◽  
Spectrum Effect

Crocus sativus L. is commonly used as functional food and medicinal herb in traditional Chinese medicine. In this study, the spectrum–effect relationship was established between HPLC fingerprints and in vitro antioxidant activity of saffron to improve the quality evaluation method of saffron. The fingerprints of 21 batches of saffron collected from different regions were assessed, and the data were further analyzed by chemometric methods, including similarity analysis, hierarchical clustering analysis, principal component analysis, and orthogonal partial least squares discriminant analysis. The spectrum–effect relationship between fingerprints and antioxidant effect of saffron was analyzed by grey relational analysis and partial least square methods to figure out the antioxidant component of saffron. Thirteen common peaks of 21 batches of saffron were included in the analysis, and peak 3 (picrocrocin), peak 7 (crocin I), and peak 10 (crocin II) were identified as the main active components responsible for antioxidant efficacy. Besides, a multi-index quality control method was developed for simultaneous determination of these three antioxidant components in saffron. Taken together, this study provided new strategies for the quality control and the development of new bioactive products of saffron in the future.

scholarly journals Development and In Vitro Evaluation of a Mucoadhesive Oral Deliverv System for Antisense Oliaonucleotides

2003 ◽  
Vol 71 (3) ◽  
pp. 165-177 ◽  
Author(s):  
Andreas Bernkop-Schnürch ◽  
Julia Telsnig ◽  
Margit Hornof
Keyword(s):  
Delivery System ◽  
Permeability Coefficient ◽  
Enzymatic Degradation ◽  
Phosphorothioate Oligonucleotide ◽  
Apparent Permeability ◽  
Release Studies ◽  
Apparent Permeability Coefficient ◽  
Permeation Studies ◽  
Membrane Bound

It was the aim of this study to develop an oral phosphorothioate oligodeoxynucleotide (PS-ODN) drug delivery system and to evaluate its properties in vitro. Results demonstrated that the 16-mer phosphorothioate oligonucleotide used was completely stable towards enzymatic degradation by secreted and membrane bound intestinal enzymes. Permeation studies with freshly excised intestinal mucosa showed a comparatively high uptake of the PS-ODN with an apparent permeability coefficient (Papp) of 8.35 ± 1.24 x 10-6 cm/sec. The PS-ODN was incorporated in a poly(acrylic acid)-cysteine carrier matrix system exhibiting high cohesive and mucoadhesive properties. Release studies demonstrated that a controlled and sustained PS-ODN release out of this delivery system could be achieved. Because of these features, the dosage form developed within this study seems to represent a promising novel tool for oral PS-ODN delivery.

scholarly journals Analysis of protein glycation in human fingernail clippings with near-infrared (NIR) spectroscopy as an alternative technique for the diagnosis of diabetes mellitus

2018 ◽  
Vol 56 (9) ◽  
pp. 1551-1558 ◽  
Author(s):  
Tinne Monteyne ◽  
Renaat Coopman ◽  
Antoine S. Kishabongo ◽  
Jonas Himpe ◽  
Bruno Lapauw ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Healthy Subjects ◽  
Near Infrared ◽  
Nir Spectroscopy ◽  
Partial Least Square ◽  
Least Square ◽  
Protein Glycation ◽  
Patients With Diabetes ◽  
Diagnosis Of Diabetes Mellitus

Abstract Background: Glycated keratin allows the monitoring of average tissue glucose exposure over previous weeks. In the present study, we wanted to explore if near-infrared (NIR) spectroscopy could be used as a non-invasive diagnostic tool for assessing glycation in diabetes mellitus. Methods: A total of 52 patients with diabetes mellitus and 107 healthy subjects were enrolled in this study. A limited number (n=21) of nails of healthy subjects were glycated in vitro with 0.278 mol/L, 0.556 mol/L and 0.833 mol/L glucose solution to study the effect of glucose on the nail spectrum. Consequently, the nail clippings of the patients were analyzed using a Thermo Fisher Antaris II Near-IR Analyzer Spectrometer and near infrared (NIR) chemical imaging. Spectral classification (patients with diabetes mellitus vs. healthy subjects) was performed using partial least square discriminant analysis (PLS-DA). Results: In vitro glycation resulted in peak sharpening between 4300 and 4400 cm−1 and spectral variations at 5270 cm−1 and between 6600 and 7500 cm−1. Similar regions encountered spectral deviations during analysis of the patients’ nails. Optimization of the spectral collection parameters was necessary in order to distinguish a large dataset. Spectra had to be collected at 16 cm−1, 128 scans, region 4000–7500 cm−1. Using standard normal variate, Savitsky-Golay smoothing (7 points) and first derivative preprocessing allowed for the prediction of the test set with 100% correct assignments utilizing a PLS-DA model. Conclusions: Analysis of protein glycation in human fingernail clippings with NIR spectroscopy could be an alternative affordable technique for the diagnosis of diabetes mellitus.

scholarly journals Transport of Corilagin, Gallic Acid, and Ellagic Acid from Fructus Phyllanthi Tannin Fraction in Caco-2 Cell Monolayers

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Xin Mao ◽  
Ling-Fang Wu ◽  
Hai-juan Zhao ◽  
Wen-Yi Liang ◽  
Wen-Jing Chen ◽  
...  
Keyword(s):  
Tight Junction ◽  
Gallic Acid ◽  
Ellagic Acid ◽  
Organic Anion ◽  
Multidrug Resistance Proteins ◽  
Apparent Permeability ◽  
Glycoprotein P ◽  
Sodium Glucose Cotransporter ◽  
Apparent Permeability Coefficient

Objective. To investigate the absorption property of the representative hydrolyzable tannin, namely corilagin, and its hydrolysates gallic acid (GA) and ellagic acid (EA) from the Fructus Phyllanthi tannin fraction (PTF)in vitro.Methods. Caco-2 cells monolayer model was established. Influences of PTF on Caco-2 cells viability were detected with MTT assay. The transport across monolayers was examined for different time points, concentrations, and secretory directions. The inhibitors of P-glycoprotein (P-gp), multidrug resistance proteins (MRPs), organic anion transporting polypeptide (OATP) and sodium/glucose cotransporter 1 (SGLT1), and tight junction modulators were used to study the transport mechanism. LC-MS method was employed to quantify the absorption concentration.Results. The apparent permeability coefficient(Papp)values of the three compounds were below 1.0 × 10−6 cm/s. The absorption of corilagin and GA were much lower than their efflux, and the uptake of both compounds was increased in the presence of inhibitors of P-gp and MRPs. The absorption of EA was decreased in the company of OATP and SGLT1 inhibitors. Moreover, the transport of corilagin, GA, and EA was enhanced by tight junction modulators.Conclusion. These observations indicated that the three compounds in PTF were transported via passive diffusion combined with protein mediated transport. P-gp and MRPs might get involved in the transport of corilagin and GA. The absorption of EA could be attributed to OATP and SGLT1 protein.

scholarly journals Amplify Antimicrobial Photo Dynamic Therapy Efficacy With Poly-beta-amino Esters (PBAEs)

2021 ◽  
Author(s):  
Stefano Perni ◽  
Emily Preedy ◽  
Polina Prokopovich
Keyword(s):  
Exposure Time ◽  
Antimicrobial Agents ◽  
Low Cost ◽  
Partial Least Square ◽  
Least Square ◽  
Partial Least Square Regression ◽  
Amino Esters ◽  
Dynamic Therapy ◽  
Photo Dynamic Therapy

Abstract Light-activated antimicrobial agents (photosensitisers) are promising alternatives to antibiotics for the treatment of skin infections and wounds through antimicrobial Photo Dynamic Therapy (aPDT); utilisation of this technique is still restricted by general low efficacy requiring long exposure time (in the order of tens of minutes) that make the treatment very resource intensive. We report for the first time the possibility of harvesting the cell penetrating properties of poly-beta-amino esters (PBAEs) in combination with toluidine blue O (TBO) to shorten aPDT exposure time. Candidates capable of inactivation rates 30 times quicker than pure TBO were discovered and further improvements through PBAE backbone optimisation could be foreseen. Efficacy of the complexes was PBAE-dependent on a combination of TBO uptake and a newly discovered and unexpected role of PBAEs on reactive species production. Chemometric approach of partial least square regression was employed to assess the critical PBAE properties involved in this newly observed phenomenon in order to elicit a possible mechanism.The superior antimicrobial performance of this new approach benefits from the use of well established, low-cost and safe dye (TBO) coupled with inexpensive, widely tested and biodegradable polymers also known to be safe. Moreover, no adverse cytotoxic effects of the PBAEs adjuvated TBO delivery have been observed on a skin cells in vitro model demonstrating the safety profile of this new technology.

scholarly journals In Silico Prediction of PAMPA Effective Permeability Using a Two-QSAR Approach

2019 ◽  
Vol 20 (13) ◽  
pp. 3170 ◽  
Author(s):  
Cheng-Ting Chi ◽  
Ming-Han Lee ◽  
Ching-Feng Weng ◽  
Max K. Leong
Keyword(s):  
Drug Discovery ◽  
Effective Permeability ◽  
Diffusion Mechanism ◽  
Qsar Model ◽  
Passive Diffusion ◽  
Partial Least Square ◽  
Least Square ◽  
Support Vector ◽  
Drug Discovery And Development

Oral administration is the preferred and predominant route of choice for medication. As such, drug absorption is one of critical drug metabolism and pharmacokinetics (DM/PK) parameters that should be taken into consideration in the process of drug discovery and development. The cell-free in vitro parallel artificial membrane permeability assay (PAMPA) has been adopted as the primary screening to assess the passive diffusion of compounds in the practical applications. A classical quantitative structure–activity relationship (QSAR) model and a machine learning (ML)-based QSAR model were derived using the partial least square (PLS) scheme and hierarchical support vector regression (HSVR) scheme to elucidate the underlying passive diffusion mechanism and to predict the PAMPA effective permeability, respectively, in this study. It was observed that HSVR executed better than PLS as manifested by the predictions of the samples in the training set, test set, and outlier set as well as various statistical assessments. When applied to the mock test, which was designated to mimic real challenges, HSVR also showed better predictive performance. PLS, conversely, cannot cover some mechanistically interpretable relationships between descriptors and permeability. Accordingly, the synergy of predictive HSVR and interpretable PLS models can be greatly useful in facilitating drug discovery and development by predicting passive diffusion.

scholarly journals Global Metabolomic and Lipidomic Analysis Reveals the Potential Mechanisms of Hemolysis Effect of Ophiopogonin D and Ophiopogonin D’ in vivo

2020 ◽  
Author(s):  
Xu Huan-Hua ◽  
Zhen-Hong Jiang ◽  
Cong-Shu Huang ◽  
Yu-Ting Sun ◽  
Long-Long Xu ◽  
...  
Keyword(s):  
Principal Component ◽  
Phospholipid Metabolism ◽  
Partial Least Square ◽  
Least Square ◽  
Practical Significance ◽  
Plasma Metabolites ◽  
Active Components ◽  
The Difference

Abstract Background: OPD and OPD' are the two main active components of Ophiopogon japonicas in Shenmai injection (SMI). Being isomers of each other, they are supposed to have similar pharmacological activities, but the actual situation is complicated. The difference of hemolytic behavior between OPD and OPD' in vivo and in vitro was discovered and reported by our group for the first time. In vitro, only OPD' showed hemolysis reaction, while in vivo, both OPD and OPD' caused hemolysis. The primary cause of hemolysis in vitro has been confirmed to be related to the difference between physical and chemical properties of OPD and OPD', but the mechanism of hemolysis in vivo is still unclear, especially the existing research are still difficult to explain why OPD shows the inconsistent hemolysis behavior in vivo and in vitro. Therefore, the study of hemolysis of OPD and OPD' in vivo is of great practical significance in response to the increase of adverse events of SMI.Methods: Aiming at the hemolysis in vivo, this manuscript adopted untargeted metabolomics and lipidomics technology to preliminarily explore the changes of plasma metabolites and lipids of OPD- and OPD'-treated rats. Metabolomics and lipidomics analyses were performed on ultra-high performance liquid chromatography (UPLC) system tandem with different mass spectrometers (MS) and different columns respectively. Multivariate statistical approaches such as principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA) were applied to screen the differential metabolites and lipids.Results: Both OPD and OPD' groups experienced hemolysis, Changes in endogenous differential metabolites and differential lipids, enrichment of differential metabolic pathways, and correlation analysis of differential metabolites and lipids all indicated that the causes of hemolysis by OPD and OPD' were closely related to the interference of phospholipid metabolism.Conclusions: This study confirmed that interference of phospholipid metabolism was the main cause of hemolysis of OPD and OPD'. This study provided a comprehensive description of metabolome and lipidomic changes under the condition of hemolysis which caused by OPD and OPD'. It can also provide clues for research on the hemolysis mechanism of traditional Chinese medicine.

scholarly journals Multivariate method for prediction of fumonisins B1 and B2 and zearalenone in Brazilian maize using Near Infrared Spectroscopy (NIR)

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244957
Author(s):  
Denize Tyska ◽  
Adriano Olnei Mallmann ◽  
Juliano Kobs Vidal ◽  
Carlos Alberto Araújo de Almeida ◽  
Luciane Tourem Gressler ◽  
...  
Keyword(s):  
Infrared Spectroscopy ◽  
Near Infrared Spectroscopy ◽  
Near Infrared ◽  
External Validation ◽  
Partial Least Square ◽  
Least Square ◽  
Partial Least Square Regression ◽  
Contamination Level ◽  
Internal Validation ◽  
Significant Difference

Fumonisins (FBs) and zearalenone (ZEN) are mycotoxins which occur naturally in grains and cereals, especially maize, causing negative effects on animals and humans. Along with the need for constant monitoring, there is a growing demand for rapid, non-destructive methods. Among these, Near Infrared Spectroscopy (NIR) has made great headway for being an easy-to-use technology. NIR was applied in the present research to quantify the contamination level of total FBs, i.e., fumonisin B1+fumonisin B2 (FB1+FB2), and ZEN in Brazilian maize. From a total of six hundred and seventy-six samples, 236 were analyzed for FBs and 440 for ZEN. Three regression models were defined: one with 18 principal components (PCs) for FB1, one with 10 PCs for FB2, and one with 7 PCs for ZEN. Partial least square regression algorithm with full cross-validation was applied as internal validation. External validation was performed with 200 unknown samples (100 for FBs and 100 for ZEN). Correlation coefficient (R), determination coefficient (R2), root mean square error of prediction (RMSEP), standard error of prediction (SEP) and residual prediction deviation (RPD) for FBs and ZEN were, respectively: 0.809 and 0.991; 0.899 and 0.984; 659 and 69.4; 682 and 69.8; and 3.33 and 2.71. No significant difference was observed between predicted values using NIR and reference values obtained by Liquid Chromatography Coupled to Tandem Mass Spectrometry (LC-MS/MS), thus indicating the suitability of NIR to rapidly analyze a large numbers of maize samples for FBs and ZEN contamination. The external validation confirmed a fair potential of the model in predicting FB1+FB2 and ZEN concentration. This is the first study providing scientific knowledge on the determination of FBs and ZEN in Brazilian maize samples using NIR, which is confirmed as a reliable alternative methodology for the analysis of such toxins.

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