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Food & Function Aug 2021The preventive and therapeutic effects of dark tea fermented by Eurotium cristatum (DTE) in glucose metabolism have been demonstrated. However, few studies have...
Potential hypoglycemic metabolites in dark tea fermented by Eurotium cristatum based on UPLC-QTOF-MS/MS combining global metabolomic and spectrum-effect relationship analyses.
The preventive and therapeutic effects of dark tea fermented by Eurotium cristatum (DTE) in glucose metabolism have been demonstrated. However, few studies have investigated comprehensive changes in the chemical composition and activity in DTE before and after fermentation. In this study, the metabolic profiling of raw samples and fermented samples was determined by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS). Furthermore, a systematic analytical strategy combining global metabolomics and the spectrum-effect relationship based on α-glucosidase inhibition was employed for screening discriminant metabolites. As a result, 15 discriminant metabolites were identified in DTE samples. Among them, 10 metabolites (4 fatty acids, 1 dyphylline derivative, 3 lysophosphatidylcholines, and 2 triterpenes) increased in relative contents and the contents of the other 5 polyphenol metabolites decreased after fermentation. These metabolites were critical constituents possibly associated with DTE's hypoglycemic activity, which also might be suitable as quality evaluation indicators. This study provided a worthy insight into the exploration of representative active constituents or quality indicators of DTE.
Topics: Aspergillus; Bioreactors; Chromatography, High Pressure Liquid; Fermentation; Hypoglycemic Agents; Metabolomics; Plant Extracts; Tandem Mass Spectrometry; Tea
PubMed: 34227645
DOI: 10.1039/d1fo00836f -
International Journal of Pharmaceutics Mar 2021The aim of this study was to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA) microparticles in which the drug is...
The aim of this study was to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA) microparticles in which the drug is dispersed in the form of tiny particles ("monolithic dispersions"). Differently sized diprophylline-loaded microparticles were prepared using a solid-in-oil-in-water solvent extraction/evaporation technique. The microparticles were characterized before and after exposure to phosphate buffer pH 7.4 at 4, 20 and 37 °C. In vitro drug release was measured from ensembles and single microparticles. GPC, DSC, SEM, gravimetric analysis, drug solubility measurements and optical microscopy were used to elucidate the importance of polymer swelling & degradation, drug dissolution and diffusion. The diprophylline was initially homogeneously distributed throughout the microparticles in the form of tiny crystals. The burst release (1st phase) was strongly temperature-dependent and likely attributable to the dissolution of drug crystals with direct surface access (potentially via tiny pores). The about constant release rate during the 2nd phase also strongly depended on the temperature. It can probably be explained by the dissolution of drug crystals in surface near regions undergoing local swelling. During the observation period, the 3rd (again rapid) drug release phase was only observed at 37 °C, and seems to be caused by substantial PLGA swelling throughout the entire microparticles. This phase starts as soon as a critical polymer molecular weight of about 25 kDa is reached: Significant amounts of water penetrate into the systems, dissolving the remaining diprophylline crystals and substantially increasing the mobility of the dissolved drug molecules. Thus, this study provides additional experimental evidence (obtained at lower temperatures) confirming the hypothesized root causes for drug release from PLGA microparticles containing dispersed drug particles.
Topics: Drug Liberation; Microspheres; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Temperature
PubMed: 33486018
DOI: 10.1016/j.ijpharm.2021.120220 -
Chemical & Pharmaceutical Bulletin 2020The high-order functions of molecular capture and chiral recognition of tea gallated catechins (-)-epigallocatechin-3-O-gallate (EGCg) in water were investigated. A... (Review)
Review
The high-order functions of molecular capture and chiral recognition of tea gallated catechins (-)-epigallocatechin-3-O-gallate (EGCg) in water were investigated. A solution of equimolar amounts of a variety of heterocyclic compounds and EGCg in water afforded adhesive precipitates containing the heterocyclic compounds and EGCg at a molar ratio of 1 : 1, based on the integrated value of NMR proton signals. The molecular capture abilities of a variety of heterocyclic compounds using EGCg from the aqueous solutions were evaluated with the ratios of the heterocyclic compounds included in the precipitates of EGCg complex to the total heterocyclic compounds used. In the H-NMR spectrum of a solution containing cyclo(L-Pro-Gly), cyclo(D-Pro-Gly), and EGCg in a DO solution, a difference in the chemical shift of the H-NMR signal for some protons of the Pro residue was observed. Judging from the crystal structures of the 2 : 2 EGCg complexes of cyclo(L-Pro-Gly), cyclo(D-Pro-Gly), the difference in the chemical shift derived mainly from a magnetic anisotropic shielding effect by the ring current from the B ring of EGCg.In the H-NMR spectrum of a solution containing the pharmaceuticals racemic (R,S)-propranolol, (R,S)-diprophylline, (R,S)-proxyphylline and EGCg in DO, splitting of the H-NMR signals of the pharmaceuticals was observed. It was suggested that the pharmaceuticals formed diastereomers of EGCg complexes, as a result chirality of the pharmaceuticals was recognized by EGCg in the DO solution.
Topics: Catechin; Deuterium Oxide; Drug Development; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Stereoisomerism
PubMed: 33268646
DOI: 10.1248/cpb.c20-00197 -
Bioorganic Chemistry Jan 2021A concise chemoenzymatic route toward enantiomerically enriched active pharmaceutical ingredients (API) - diprophylline and xanthinol nicotinate - is reported for the...
A concise chemoenzymatic route toward enantiomerically enriched active pharmaceutical ingredients (API) - diprophylline and xanthinol nicotinate - is reported for the first time. The decisive step is an enantioselective lipase-mediated methanolysis of racemic chlorohydrin-synthon acetate, namely 1-chloro-3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propan-2-yl acetate, performed under kinetically-controlled conditions on a preparative 500 mg-scale. The best results in terms of reaction enantioselectivity (E = 14) were obtained for the enantiomers resolution performed with lipase type B from Candida antarctica immobilized on acrylic resin (CAL-B, Novozym 435) suspended in homophasic acetonitrile-methanol mixture. The elaborated biocatalytic system furnished the key chlorohydrin intermediate (in 71% ee and 38% yield), which was then smoothly converted into enantioenriched active agents: (R)-(-)-diprophylline (57% ee) and (S)-(+)-xanthinol nicotinate (65% ee). To support the assignment of absolute configurations of EKR-products as well as to confirm the stereochemical outcome of the remaining reaction steps, docking studies toward the prediction of enantiomers binding selectivity in CAL-B active site as well as the respective chemical correlations with enantiomerically enriched analytical standards obtained from commercially available (R)-(-)-epichlorohydrin, were applied. In addition, single-crystal X-ray diffraction (XRD) analyses were performed for the synthesized optically active APIs furnishing by this manner a first crystal structures of nicotinic acid salt of xanthinol.
Topics: Basidiomycota; Biocatalysis; Dyphylline; Enzymes, Immobilized; Esterification; Fungal Proteins; Hydrogen Bonding; Hydrolysis; Lipase; Molecular Docking Simulation; Protein Binding; Stereoisomerism; Xanthinol Niacinate
PubMed: 33229120
DOI: 10.1016/j.bioorg.2020.104448 -
Journal of Biomolecular Structure &... Mar 2022In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of a pulmonary disease called COVID-19, which...
In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of a pulmonary disease called COVID-19, which killed thousands of people worldwide. Therefore, the necessity to find out the potential therapeutic pharmaceuticals is imperious. This study investigates the inhibitory effect of SARS-CoV-2 3-chymotrypsin-like protease (3CL) using caffeine and caffeine-containing pharmaceuticals (3CPs) based on molecular dynamics simulations and free energy calculations by means of molecular mechanics-Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics-generalized-Born surface area (MMGBSA). Of these 3CPs, seven drugs approved by the US-Food and Drug Administration have shown a good binding affinity to the catalytic residues of 3CL of His and Cys: caffeine, theophylline, dyphylline, pentoxifylline, linagliptin, bromotheophylline and istradefylline. Their binding affinity score ranged from -4.9 to -8.6 kcal/mol. The molecular dynamic simulation in an aqueous solution of docked complexes demonstrated that the 3CPs conformations bound to the active sites of 3CL during 200 ns molecular dynamics simulations. The free energy of binding also confirms the stability of the 3CPs-3CL complexes. To our knowledge, this study shows for the first time very inexpensive drugs available in large quantities that can be potential inhibitors against 3CL. In particular, the repurposing of linagliptin, and caffeine are recommended for COVID-19 treatment after and clinical trial validation.Communicated by Ramaswamy H. Sarma.
Topics: Caffeine; Chymases; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33094705
DOI: 10.1080/07391102.2020.1835732 -
Journal of Molecular Graphics &... Nov 2020Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective...
Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future.
Topics: Amino Acid Motifs; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Antiviral Agents; Betacoronavirus; COVID-19; Carbazoles; Catalytic Domain; Coronavirus Infections; Drug Repositioning; Dyphylline; Host-Pathogen Interactions; Humans; Hydroxamic Acids; Ligands; Molecular Docking Simulation; Pandemics; Paromomycin; Pemetrexed; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; SARS-CoV-2; Small Molecule Libraries; Structure-Activity Relationship; Thermodynamics
PubMed: 32739642
DOI: 10.1016/j.jmgm.2020.107697 -
Bioscience Reports Jun 2020Serous ovarian cancer is one of the most fatal gynecological tumors with an extremely low 5-year survival rate. Most patients are diagnosed at an advanced stage with...
Serous ovarian cancer is one of the most fatal gynecological tumors with an extremely low 5-year survival rate. Most patients are diagnosed at an advanced stage with wide metastasis. The dysregulation of genes serves an important role in the metastasis progression of ovarian cancer. Differentially expressed genes (DEGs) between primary tumors and metastases of serous ovarian cancer were screened out in the gene expression profile of GSE73168 from Gene Expression Omnibus (GEO). Cytoscape plugin cytoHubba and weighted gene co-expression network analysis (WGCNA) were utilized to select hub genes. Univariate and multivariate Cox regression analyses were used to screen out prognosis-associated genes. Furthermore, the Oncomine validation, prognostic analysis, methylation mechanism, gene set enrichment analysis (GSEA), TIMER database analysis and administration of candidate molecular drugs were conducted for hub genes. Nine hundred and fifty-seven DEGs were identified in the gene expression profile of GSE73168. After using Cytoscape plugin cytoHubba, 83 genes were verified. In co-expression network, the blue module was most closely related to tumor metastasis. Furthermore, the genes in Cytoscape were analyzed, showing that the blue module and screened 17 genes were closely associated with tumor metastasis. Univariate and multivariate Cox regression revealed that the age, stage and STMN2 were independent prognostic factors. The Cancer Genome Atlas (TCGA) suggested that the up-regulated expression of STMN2 was related to poor prognosis of ovarian cancer. Thus, STMN2 was considered as a new key gene after expression validation, survival analysis and TIMER database validation. GSEA confirmed that STMN2 was probably involved in ECM receptor interaction, focal adhesion, TGF beta signaling pathway and MAPK signaling pathway. Furthermore, three candidate small molecule drugs for tumor metastasis (diprophylline, valinomycin and anisomycin) were screened out. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot showed that STMN2 was highly expressed in ovarian cancer tissue and ovarian cancer cell lines. Further studies are needed to investigate these prognosis-associated genes for new therapy target.
Topics: Age Factors; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Databases, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Protein Interaction Maps; Signal Transduction; Stathmin
PubMed: 32510146
DOI: 10.1042/BSR20194324 -
AAPS PharmSciTech May 2020The aim of this study was to evaluate the potential of a cross-linked pregelatinized potato starch (PREGEFLO® PI10) as matrix former for controlled release tablets....
The aim of this study was to evaluate the potential of a cross-linked pregelatinized potato starch (PREGEFLO® PI10) as matrix former for controlled release tablets. Different types of tablets loaded with diprophylline, diltiazem HCl or theophylline were prepared by direct compression of binary drug/polymer blends. The drug content was varied from 20 to 50%. Two hydroxypropyl methylcellulose grades (HPMC K100LV and K100M) were studied as alternative matrix formers. Drug release was measured in a variety of release media using different types of experimental set-ups. This includes 0.1 N HCl, phosphate buffer pH 6.8 and water, optionally containing different amounts of NaCl, sucrose, ethanol or pancreatin, fasted state simulated gastric fluid, fed state simulated gastric fluid, fasted state simulated intestinal fluid, fed state simulated intestinal fluid as well as media simulating the conditions in the colon of healthy subjects and patients suffering from Crohn's disease. The USP apparatuses I/II/III were used under a range of operating conditions and optionally coupled with the simulation of additional mechanical stress. Importantly, the drug release kinetics was not substantially affected by the investigated environmental conditions from tablets based on the cross-linked pregelatinized potato starch, similar to HPMC tablets. However, in contrast to the latter, the starch-based tablets roughly kept their shape upon exposure to the release media (they "only" increased in size) during the observation period, and the water penetration into the systems was much less pronounced. Thus, the investigated cross-linked pregelatinized potato starch offers an interesting potential as matrix former in controlled release tablets.
Topics: Delayed-Action Preparations; Diltiazem; Drug Liberation; Gelatin; Humans; Hypromellose Derivatives; Solanum tuberosum; Starch; Tablets; Theophylline
PubMed: 32436061
DOI: 10.1208/s12249-020-01674-4 -
Pharmaceutics Nov 2019The subject of our research is the optimization of direct compression (DC), controlled release drug matrices comprising chitosan/xanthan gum. The foregoing is considered...
The subject of our research is the optimization of direct compression (DC), controlled release drug matrices comprising chitosan/xanthan gum. The foregoing is considered from two main perspectives; the use of low molecular weight chitosan (LCS) with xanthan gum (XG) and the determination of important attributes for direct compression of the mixtures of the two polymers. Powder flow, deformation behaviour, and work of compression parameters were used to characterize powder and tableting properties. Compression pressure and LCS content within the matrix were investigated for their influence on the crushing strength of the tablets produced. Response surface methodology (RSM) was applied to determine the optimum parameters required for DC of the matrices investigated. Results confirm the positive contribution of LCS in enhancing powder compressibility and crushing strength of the resultant compacts. Compactibility of the XG/LCS mixtures was found to be more sensitive to applied compression pressure than LCS content. LCS can be added at concentrations as low as 15% / to achieve hard compacts, as indicated by the RSM results. The introduction of the plasticity factor, using LCS, to the fragmenting material XG was the main reason for the high volume reduction and reduced porosity of the polymer mixture. Combinations of XG with other commonly utilized polymers in controlled release studies such as glucosamine, hydroxypropyl methylcellulose (HPMC), Na alginate (ALG), guar gum, lactose and high molecular weight (HMW) chitosan were also used; all the foregoing polymers failed to reduce the matrix porosity beyond a certain compression pressure. Application of the LCS/XG mixture, at its optimum composition, for the controlled release of two model drugs (metoprolol succinate and dyphylline) was examined. The XG/LCS matrix at 15% w/w LCS content was found to control the release of metoprolol succinate and dyphylline. The former preparation confirmed the strong influence of compression pressure on changing the drug release profile. The latter preparation showed the ability of XG/LCS to extend the drug release at a fixed rate for 12 h of dissolution time after which the release became slightly slower.
PubMed: 31726799
DOI: 10.3390/pharmaceutics11110603 -
International Journal of Pharmaceutics Dec 2019The aim of this study was to better understand the root causes for the (up to) 3 drug release phases observed with poly (lactic-co-glycolic acid) (PLGA) microparticles...
The aim of this study was to better understand the root causes for the (up to) 3 drug release phases observed with poly (lactic-co-glycolic acid) (PLGA) microparticles containing diprophylline particles: The 1st release phase ("burst release"), 2nd release phase (with an "about constant release rate") and 3rd release phase (which is again rapid and leads to complete drug exhaust). The behavior of single microparticles was monitored upon exposure to phosphate buffer pH 7.4, in particular with respect to their drug release and swelling behaviors. Diprophylline-loaded PLGA microparticles were prepared with a solid-in-oil-in-water solvent extraction/evaporation method. Tiny drug crystals were rather homogeneously distributed throughout the polymer matrix after manufacturing. Batches with "small" (63 µm), "medium-sized" (113 µm) and "large" (296 µm) microparticles with a practical drug loading of 5-7% were prepared. Importantly, each microparticle releases the drug "in its own way", depending on the exact distribution of the tiny drug crystals within the system. During the burst release, drug crystals with direct surface access rapidly dissolve. During the 2nd release phase tiny drug crystals (often) located in surface near regions which undergo swelling, are likely released. During the 3rd release phase, the entire microparticle undergoes substantial swelling. This results in high quantities of water present throughout the system, which becomes "gel-like". Consequently, the drug crystals dissolve, and the dissolved drug molecules rather rapidly diffuse through the highly swollen polymer gel.
Topics: Chemistry, Pharmaceutical; Crystallization; Drug Carriers; Drug Compounding; Drug Liberation; Dyphylline; Microspheres; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Solvents; Water
PubMed: 31726196
DOI: 10.1016/j.ijpharm.2019.118819