@article{KrannichThereseBroscheitetal.2012, author = {Krannich, Jens-Holger and Therese, Tobias and Broscheit, Jens and Leyh, Rainer and M{\"u}llges, Wolfgang}, title = {Diabetes severely affects attentional performance after coronary artery bypass grafting}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75320}, year = {2012}, abstract = {Background: Diabetes is a risk factor for (micro) vascular damage of the brain, too. Therefore cognitive performance after coronary artery bypass grafting may be hypothesized worse in diabetics. To avoid observational errors a reliable tool for testing attentional performance was used. We evaluated whether diabetes mellitus disposes to distinct cognitive dysfunction after coronary artery bypass grafting (CABG). Methods: Three aspects in attentional performance were prospectively tested with three different tests (alertness: composed of un-cued and cued reaction, divided attention, and selective attention) by a computerized tool one day before and seven days after CABG in a highly selected cohort of 30 males, 10 of whom had diabetes. Statistical comparisons were done with analysis of variance for repeated measurements and Fisher´s LSD. Results: Prior to CABG there was no statistically meaningful difference between diabetics and non-diabetics. Postoperatively, diabetic patients performed significantly worse than non-diabetics in tests for un-cued (p=0.01) and cued alertness (p=0.03). Test performance in divided attention was worse after CABG but independent of diabetes status. Selective attention was neither affected by diabetes status nor by CABG itself. Conclusions: Diabetes may have an impact on cognitive performance after CABG. More severe deficits in alertness may point to underlying microvascular disease.}, subject = {Medizin}, language = {en} } @article{ShityakovSohajdaPuskasetal.2014, author = {Shityakov, Sergey and Sohajda, Tam{\´a}s and Puskas, Istav{\´a}n and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert}, title = {Ionization States, Cellular Toxicity and Molecular Modeling Studies of Midazolam Complexed with Trimethyl-β-Cyclodextrin}, series = {Molecules}, volume = {19}, journal = {Molecules}, number = {10}, doi = {10.3390/molecules191016861}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119186}, pages = {16861-76}, year = {2014}, abstract = {We investigated the ionization profiles for open-ring (OR) and closed-ring (CR) forms of midazolam and drug-binding modes with heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin (trimethyl-β-cyclodextrin; TRIMEB) using molecular modeling techniques and quantum mechanics methods. The results indicated that the total net charges for different molecular forms of midazolam tend to be cationic for OR and neutral for CR at physiological pH levels. The thermodynamic calculations demonstrated that CR is less water-soluble than OR, mainly due to the maximal solvation energy (ΔG(CR)(solv = -9.98 kcal·mol ⁻¹), which has a minimal ΔG(OR)(solv) of -67.01 kcal·mol⁻¹. A cell viability assay did not detect any signs of TRIMEB and OR/CR-TRIMEB complex toxicity on the cEND cells after 24 h of incubation in either Dulbecco's Modified Eagles Medium or in heat-inactivated human serum. The molecular docking studies identified the more flexible OR form of midazolam as being a better binder to TRIMEB with the fluorophenyl ring introduced inside the amphiphilic cavity of the host molecule. The OR binding affinity was confirmed by a minimal Gibbs free energy of binding (ΔG(bind)) value of -5.57 ± 0.02 kcal·mol⁻¹, an equilibrium binding constant (K(b)) of 79.89 ± 2.706 μM, and a ligand efficiency index (LE(lig)) of -0.21 ± 0.001. Our current data suggest that in order to improve the clinical applications of midazolam via its complexation with trimethyl-β-cyclodextrin to increase drug's overall aqueous solubility, it is important to concern the different forms and ionization states of this anesthetic. All mean values are indicated with their standard deviations.}, language = {en} } @article{ShityakovPuskasRoeweretal.2014, author = {Shityakov, Sergey and Pusk{\´a}s, Istv{\´a}n and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens}, title = {Three-dimensional quantitative structure-activity relationship and docking studies in a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors}, series = {Advances and Applications in Bioinformatics and Chemistry}, volume = {7}, journal = {Advances and Applications in Bioinformatics and Chemistry}, doi = {10.2147/AABC.S56478}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120226}, pages = {11-21}, year = {2014}, abstract = {The cytochrome P450 (CYP)3A4 enzyme affects the metabolism of most drug-like substances, and its inhibition may influence drug safety. Modulation of CYP3A4 by flavonoids, such as anthocyanins, has been shown to inhibit the mutagenic activity of mammalian cells. Considering the previous investigations addressing CYP3A4 inhibition by these substances, we studied the three-dimensional quantitative structure-activity relationship (3D-QSAR) in a series of anthocyanin derivatives as CYP3A4 inhibitors. For the training dataset (n=12), comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) yielded crossvalidated and non-crossvalidated models with a q (2) of 0.795 (0.687) and r (2) of 0.962 (0.948), respectively. The models were also validated by an external test set of four compounds with r (2) of 0.821 (CoMFA) and r (2) of 0.812 (CoMSIA). The binding affinity modes associated with experimentally derived IC50 (half maximal inhibitory concentration) values were confirmed by molecular docking into the CYP3A4 active site with r (2) of 0.66. The results obtained from this study are useful for a better understanding of the effects of anthocyanin derivatives on inhibition of carcinogen activation and cellular DNA damage.}, language = {en} } @article{ShityakovBroscheitFoerster2013, author = {Shityakov, Sergey and Broscheit, Jens and F{\"o}rster, Carola}, title = {Multidrug resistance protein P-gp interaction with nanoparticles (fullerenes and carbon nanotube) to assess their drug delivery potential: a theoretical molecular docking study.}, series = {International journal of computational biology and drug design}, volume = {6}, journal = {International journal of computational biology and drug design}, number = {4}, doi = {10.1504/IJCBDD.2013.056801}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132089}, pages = {343-357}, year = {2013}, abstract = {P-glycoprotein (P-gp)-mediated efflux system plays an important role to maintain chemical balance in mammalian cells for endogenous and exogenous chemical compounds. However, despite the extensive characterisation of P-gp potential interaction with drug-like molecules, the interaction of carbon nanoparticles with this type of protein molecule is poorly understood. Thus, carbon nanoparticles were analysed, such as buckminsterfullerenes (C20, C60, C70), capped armchair single-walled carbon nanotube (SWCNT or C168), and P-gp interactions using different molecular docking techniques, such as gradient optimisation algorithm (ADVina), Lamarckian genetic algorithm (FastDock), and shape-based approach (PatchDock) to estimate the binding affinities between these structures. The theoretical results represented in this work show that fullerenes might be P-gp binders because of low levels of Gibbs free energy of binding (ΔG) and potential of mean force (PMF) values. Furthermore, the SWCNT binding is energetically unfavourable, leading to a total decrease in binding affinity by elevation of the residual area (Ares), which also affects the π-π stacking mechanisms. Further, the obtained data could potentially call experimental studies using carbon nanostructures, such as SWCNT for development of drug delivery vehicles, to administer and assess drug-like chemical compounds to the target cells since organisms probably did not develop molecular sensing elements to detect these types of carbon molecules.}, language = {en} } @article{ShityakovPuskasPapaietal.2015, author = {Shityakov, Sergey and Pusk{\´a}s, Istv{\´a}n and P{\´a}pai, Katalin and Salvador, Ellaine and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert}, title = {Sevoflurane-sulfobutylether-\(\beta\)-cyclodextrin complex: preparation, characterization, cellular toxicity, molecular modeling and blood-brain barrier transport studies}, series = {Molecules}, volume = {20}, journal = {Molecules}, doi = {10.3390/molecules200610264}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148543}, pages = {10264-10279}, year = {2015}, abstract = {The objective of the present investigation was to study the ability of sulfobutylether-\(\beta\)-cyclodextrin (SBECD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBE\(\beta\)CD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (P\(_{app}\)). In addition, SEV binding affinity to SBE\(\beta\)CD was confirmed by a minimal Gibbs free energy of binding (ΔG\(_{bind}\)) value of -1.727 ± 0.042 kcal・mol\(^{-1}\) and an average binding constant (K\(_{b}\)) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.}, language = {en} } @article{ShityakovRoewerFoersteretal.2017, author = {Shityakov, Sergey and Roewer, Norbert and F{\"o}rster, Carola and Broscheit, Jens-Albert}, title = {In silico modeling of indigo and Tyrian purple single-electron nano-transistors using density functional theory approach}, series = {Nanoscale Research Letters}, volume = {12}, journal = {Nanoscale Research Letters}, number = {439}, doi = {10.1186/s11671-017-2193-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158332}, year = {2017}, abstract = {The purpose of this study was to develop and implement an in silico model of indigoid-based single-electron transistor (SET) nanodevices, which consist of indigoid molecules from natural dye weakly coupled to gold electrodes that function in a Coulomb blockade regime. The electronic properties of the indigoid molecules were investigated using the optimized density-functional theory (DFT) with a continuum model. Higher electron transport characteristics were determined for Tyrian purple, consistent with experimentally derived data. Overall, these results can be used to correctly predict and emphasize the electron transport functions of organic SETs, demonstrating their potential for sustainable nanoelectronics comprising the biodegradable and biocompatible materials.}, language = {en} } @article{ChenLotzRoeweretal.2018, author = {Chen, Shasha and Lotz, Christopher and Roewer, Norbert and Broscheit, Jens-Albert}, title = {Comparison of volatile anesthetic-induced preconditioning in cardiac and cerebral system: molecular mechanisms and clinical aspects}, series = {European Journal of Medical Research}, volume = {23}, journal = {European Journal of Medical Research}, number = {10}, doi = {10.1186/s40001-018-0308-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175509}, year = {2018}, abstract = {Volatile anesthetic-induced preconditioning ( APC) has shown to have cardiac and cerebral protective properties in both pre-clinical models and clinical trials. Interestingly, accumulating evidences demonstrate that, except from some specific characters, the underlying molecular mechanisms of APC-induced protective effects in myocytes and neurons are very similar; they share several major intracellular signaling pathways, including mediating mitochondrial function, release of inflammatory cytokines and cell apoptosis. Among all the experimental results, cortical spreading depolarization is a relative newly discovered cellular mechanism of APC, which, however, just exists in central nervous system. Applying volatile anesthetic preconditioning to clinical practice seems to be a promising cardio- and neuroprotective strategy. In this review, we also summarized and discussed the results of recent clinical research of APC. Despite all the positive experimental evidences, large-scale, long-term, more precisely controlled clinical trials focusing on the perioperative use of volatile anesthetics for organ protection are still needed.}, language = {en} } @article{EsmaeilpourBroscheitShityakov2022, author = {Esmaeilpour, Donya and Broscheit, Jens Albert and Shityakov, Sergey}, title = {Cyclodextrin-based polymeric materials bound to corona protein for theranostic applications}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {21}, issn = {1422-0067}, doi = {10.3390/ijms232113505}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297399}, year = {2022}, abstract = {Cyclodextrins (CDs) are cyclic oligosaccharide structures that could be used for theranostic applications in personalized medicine. These compounds have been widely utilized not only for enhancing drug solubility, stability, and bioavailability but also for controlled and targeted delivery of small molecules. These compounds can be complexed with various biomolecules, such as peptides or proteins, via host-guest interactions. CDs are amphiphilic compounds with water-hating holes and water-absorbing surfaces. Architectures of CDs allow the drawing and preparation of CD-based polymers (CDbPs) with optimal pharmacokinetic and pharmacodynamic properties. These polymers can be cloaked with protein corona consisting of adsorbed plasma or extracellular proteins to improve nanoparticle biodistribution and half-life. Besides, CDs have become famous in applications ranging from biomedicine to environmental sciences. In this review, we emphasize ongoing research in biomedical fields using CD-based centered, pendant, and terminated polymers and their interactions with protein corona for theranostic applications. Overall, a perusal of information concerning this novel approach in biomedicine will help to implement this methodology based on host-guest interaction to improve therapeutic and diagnostic strategies.}, language = {en} } @article{WilhelmsBroscheitShityakov2023, author = {Wilhelms, Benedikt and Broscheit, Jens and Shityakov, Sergey}, title = {Chemical analysis and molecular modelling of cyclodextrin-formulated propofol and its sodium salt to improve drug solubility, stability and pharmacokinetics (cytogenotoxicity)}, series = {Pharmaceuticals}, volume = {16}, journal = {Pharmaceuticals}, number = {5}, issn = {1424-8247}, doi = {10.3390/ph16050667}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313705}, year = {2023}, abstract = {Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-β-cyclodextrin (HPβCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPβCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPβCD than for Na-propofolate/HPβCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.}, language = {en} }