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- ItemConductive Gas Plasma Treatment Augments Tumor Toxicity of Ringer’s Lactate Solutions in a Model of Peritoneal Carcinomatosis(Basel : MDPI, 2022) Miebach, Lea; Freund, Eric; Cecchini, Alessandra Lourenço; Bekeschus, SanderReactive species generated by medical gas plasma technology can be enriched in liquids for use in oncology targeting disseminated malignancies, such as metastatic colorectal cancer. Notwithstanding, reactive species quantities depend on the treatment mode, and we recently showed gas plasma exposure in conductive modes to be superior for cancer tissue treatment. However, evidence is lacking that such a conductive mode also equips gas plasma-treated liquids to confer augmented intraperitoneal anticancer activity. To this end, employing atmospheric pressure argon plasma jet kINPen-treated Ringer’s lactate (oxRilac) in a CT26-model of colorectal peritoneal carcinomatosis, we tested repeated intraabdominal injection of such remotely or conductively oxidized liquid for antitumor control and immunomodulation. Enhanced reactive species formation in conductive mode correlated with reduced tumor burden in vivo, emphasizing the advantage of conduction over the free mode for plasma-conditioned liquids. Interestingly, the infiltration of lymphocytes into the tumors was equally enhanced by both treatments. However, significantly lower levels of interleukin (IL)4 and IL13 and increased levels of IL2 argue for a shift in intratumoral T-helper cell subpopulations correlating with disease control. In conclusion, our data argue for using conductively over remotely prepared plasma-treated liquids for anticancer treatment.
- ItemCryo-printed microfluidics enable rapid prototyping for optical-cell analysis(Heidelberg : Springer, 2022) Garmasukis, Rokas; Hackl, Claudia; Dusny, Christian; Elsner, Christian; Charvat, Ales; Schmid, Andreas; Abel, BerndThis paper highlights an innovative, low-cost rapid-prototyping method for generating microfluidic chips with extraordinary short fabrication times of only a few minutes. Microchannels and inlet/outlet ports are created by controlled deposition of aqueous microdroplets on a cooled surface resulting in printed ice microstructures, which are in turn coated with a UV-curable acrylic cover layer. Thawing leaves an inverse imprint as a microchannel structure. For an exemplary case, we applied this technology for creating a microfluidic chip for cell-customized optical-cell analysis. The chip design includes containers for cell cultivation and analysis. Container shape, length, position, and angle relative to the main channel were iteratively optimized to cultivate and analyze different cell types. With the chip, we performed physiological analyses of morphologically distinct prokaryotic Corynebacterium glutamicum DM1919, eukaryotic Hansenula polymorpha RB11 MOX-GFP, and phototrophic Synechocystis sp. PCC 6803 cells via quantitative time-lapse fluorescence microscopy. The technology is not limited to rapid prototyping of complex biocompatible microfluidics. Further exploration may include printing with different materials other than water, printing on other substrates in-situ biofunctionalization, the inclusion of electrodes and many other applications.
- ItemSynthesis, in Vitro Profiling, and in Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors(Washington, DC : ACS, 2022) Codony, Sandra; Entrena, José M.; Calvó-Tusell, Carla; Jora, Beatrice; González-Cano, Rafael; Osuna, Sílvia; Corpas, Rubén; Morisseau, Christophe; Pérez, Belén; Barniol-Xicota, Marta; Griñán-Ferré, Christian; Pérez, Concepción; Rodríguez-Franco, María Isabel; Martínez, Antón L.; Loza, M. Isabel; Pallàs, Mercè; Verhelst, Steven H. L.; Sanfeliu, Coral; Feixas, Ferran; Hammock, Bruce D.; Brea, José; Cobos, Enrique J.; Vázquez, SantiagoThe soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.
- ItemRole of actin cytoskeleton in cargo delivery mediated by vertically aligned silicon nanotubes(London : Biomed Central, 2022) Chen, Yaping; Yoh, Hao Zhe; Shokouhi, Ali-Reza; Murayama, Takahide; Suu, Koukou; Morikawa, Yasuhiro; Voelcker, Nicolas H.; Elnathan, RoeyNanofabrication technologies have been recently applied to the development of engineered nano–bio interfaces for manipulating complex cellular processes. In particular, vertically configurated nanostructures such as nanoneedles (NNs) have been adopted for a variety of biological applications such as mechanotransduction, biosensing, and intracellular delivery. Despite their success in delivering a diverse range of biomolecules into cells, the mechanisms for NN-mediated cargo transport remain to be elucidated. Recent studies have suggested that cytoskeletal elements are involved in generating a tight and functional cell–NN interface that can influence cargo delivery. In this study, by inhibiting actin dynamics using two drugs—cytochalasin D (Cyto D) and jasplakinolide (Jas), we demonstrate that the actin cytoskeleton plays an important role in mRNA delivery mediated by silicon nanotubes (SiNTs). Specifically, actin inhibition 12 h before SiNT-cellular interfacing (pre-interface treatment) significantly dampens mRNA delivery (with efficiencies dropping to 17.2% for Cyto D and 33.1% for Jas) into mouse fibroblast GPE86 cells, compared to that of untreated controls (86.9%). However, actin inhibition initiated 2 h after the establishment of GPE86 cell–SiNT interface (post-interface treatment), has negligible impact on mRNA transfection, maintaining > 80% efficiency for both Cyto D and Jas treatment groups. The results contribute to understanding potential mechanisms involved in NN-mediated intracellular delivery, providing insights into strategic design of cell–nano interfacing under temporal control for improved effectiveness.
- ItemNano-in-Microparticles for Aerosol Delivery of Antibiotic-Loaded, Fucose-Derivatized, and Macrophage-Targeted Liposomes to Combat Mycobacterial Infections: In Vitro Deposition, Pulmonary Barrier Interactions, and Targeted Delivery(Weinheim : Wiley-VCH, 2022) Huck, Benedikt C.; Thiyagarajan, Durairaj; Bali, Aghiad; Boese, Annette; Besecke, Karen F.W.; Hozsa, Constantin; Gieseler, Robert K.; Furch, Marcus; Carvalho‐Wodarz, Cristiane; Waldow, Franziska; Schwudke, Dominik; Metelkina, Olga; Titz, Alexander; Huwer, Hanno; Schwarzkopf, Konrad; Hoppstädter, Jessica; Kiemer, Alexandra K.; Koch, Marcus; Loretz, Brigitta; Lehr, Claus‐MichaelNontuberculous mycobacterial infections rapidly emerge and demand potent medications to cope with resistance. In this context, targeted loco-regional delivery of aerosol medicines to the lungs is an advantage. However, sufficient antibiotic delivery requires engineered aerosols for optimized deposition. Here, the effect of bedaquiline-encapsulating fucosylated versus nonfucosylated liposomes on cellular uptake and delivery is investigated. Notably, this comparison includes critical parameters for pulmonary delivery, i.e., aerosol deposition and the noncellular barriers of pulmonary surfactant (PS) and mucus. Targeting increases liposomal uptake into THP-1 cells as well as peripheral blood monocyte- and lung-tissue derived macrophages. Aerosol deposition in the presence of PS, however, masks the effect of active targeting. PS alters antibiotic release that depends on the drug's hydrophobicity, while mucus reduces the mobility of nontargeted more than fucosylated liposomes. Dry-powder microparticles of spray-dried bedaquiline-loaded liposomes display a high fine particle fraction of >70%, as well as preserved liposomal integrity and targeting function. The antibiotic effect is maintained when deposited as powder aerosol on cultured Mycobacterium abscessus. When treating M. abscessus infected THP-1 cells, the fucosylated variant enabled enhanced bacterial killing, thus opening up a clear perspective for the improved treatment of nontuberculous mycobacterial infections.
- ItemConsensusPrime—A Bioinformatic Pipeline for Ideal Consensus Primer Design(Basel : MDPI, 2022) Collatz, Maximilian; Braun, Sascha D.; Monecke, Stefan; Ehricht, RalfBackground: High-quality oligonucleotides for molecular amplification and detection procedures of diverse target sequences depend on sequence homology. Processing input sequences and identifying homogeneous regions in alignments can be carried out by hand only if they are small and contain sequences of high similarity. Finding the best regions for large and inhomogeneous alignments needs to be automated. Results: The ConsensusPrime pipeline was developed to sort out redundant and technical interfering data in multiple sequence alignments and detect the most homologous regions from multiple sequences. It automates the prediction of optimal consensus primers for molecular analytical and sequence-based procedures/assays. Conclusion: ConsensusPrime is a fast and easy-to-use pipeline for predicting optimal consensus primers that is executable on local systems without depending on external resources and web services. An implementation in a Docker image ensures platform-independent executability and installability despite the combination of multiple programs. The source code and installation instructions are publicly available on GitHub.
- ItemEndothelial cell spreading on lipid bilayers with combined integrin and cadherin binding ligands(Amsterdam [u.a.] : Elsevier, 2022) Koçer, Gülistan; Albino, Inês M.C.; Verheijden, Mark L.; Jonkheijm, PascalEndothelial cells play a central role in the vascular system, where their function is tightly regulated by both cell-extracellular matrix (e.g., via integrins) and cell–cell interactions (e.g., via cadherins). In this study, we incorporated cholesterol-modified integrin and N-cadherin peptide binding ligands in fluid supported lipid bilayers. Human umbilical vein endothelial cell adhesion, spreading and vinculin localization in these cells were dependent on ligand density. One composition led to observe a higher extent of cell spreading, where cells exhibited extensive lamellipodia formation and a qualitatively more distinct N-cadherin localization at the cell periphery, which is indicative of N-cadherin clustering and a mimic of cell–cell contact formation. The results can be used to reconstitute the endothelial-pericyte interface on biomedical devices and materials.