Review
Chemistry, Medicinal
Yuan-Yuan Gao, Wen Tian, Hui-Nan Zhang, Yang Sun, Jing-Ru Meng, Wei Cao, Xiao-Qiang Li
Summary: TRPCs channels play crucial roles in human physiological and pathological processes, but finding selective TRPCs modulators remains challenging. Further exploration for more effective and selective TRPCs modulators is needed.
ARCHIVES OF PHARMACAL RESEARCH
(2021)
Article
Cardiac & Cardiovascular Systems
Xin Wen, Yidi Peng, Mengru Gao, Yuzhong Zhu, Yifei Zhu, Fan Yu, Tingting Zhou, Jing Shao, Lei Feng, Xin Ma
Summary: This study demonstrates that TRPC1 improves cardiac function after myocardial infarction by promoting angiogenesis. The study explores the regulatory mechanisms of HIF-1 alpha and MEK/ERK, and finds that treatment with dimethyloxaloylglycine has a protective effect on myocardial infarction.
JOURNAL OF THE AMERICAN HEART ASSOCIATION
(2022)
Article
Chemistry, Multidisciplinary
David Roesel, Maksim Eremchev, Chetan S. Poojari, Jochen S. Hub, Sylvie Roke
Summary: A direct link between membrane potential fluctuations and divalent ion transport has been discovered, and it has been shown through molecular dynamics simulations and experimental results that pore formation induced by an ion-induced electrostatic field is a viable mechanism for unassisted ion transport.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Cell Biology
Katelyn E. Sadler, Francie Moehring, Stephanie Shiers, Lauren J. Laskowski, Alexander R. Mikesell, Zakary R. Plautz, Allison N. Brezinski, Christina M. Mecca, Gregory Dussor, Theodore J. Price, John D. McCorvy, Cheryl L. Stucky
Summary: The study identified TRPC5 as a key contributor to tactile and spontaneous pain in multiple rodent pain models, particularly in conditions characterized by elevated LPC concentrations. 75% of human sensory neurons express TRPC5, and its activity is directly modulated by LPC.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Review
Cell Biology
Bethan A. Cole, Esther B. E. Becker
Summary: The TRPC3 channel is a crucial player in calcium signaling and is regulated by various endogenous and exogenous factors. Recent studies have advanced our understanding of the regulatory mechanisms of TRPC3, which has implications for the development of therapeutic interventions for diseases associated with this channel.
Article
Chemistry, Medicinal
Kevin D. Phelan, U. Thaung Shwe, Fang Zheng
Summary: This study investigated the effects of TRPC4 modulators in the lateral septum and found pharmacological differences between homomeric TRPC4 channels and heteromeric TRPC1/4 channels, suggesting a need for reevaluation of the current drug development strategy regarding TRPC1/4/5.
Article
Chemistry, Medicinal
Yin-Ying Mak, Bi-Juin Loong, Paul Millns, Claudia C. Bauer, Robin S. Bon, Yvonne Mbaki, Fong-Kai Lee, Kuan-Hon Lim, Cin Kong, Sue-Mian Then, Kang-Nee Ting
Summary: This study investigated the vasorelaxant effects of schwarzinicine A, a newly reported alkaloid from Ficus schwarzii Koord. The results showed that schwarzinicine A exerts its significant vasorelaxant effect by blocking multiple TRPC channels and L-type VGCC.
PHYTOTHERAPY RESEARCH
(2022)
Article
Medicine, Research & Experimental
Bei Miao, Yue Yin, Guangtong Mao, Benhuo Zhao, Jiaojiao Wu, Hengliang Shi, Sujuan Fei
Summary: This study revealed the involvement of BDNF in driving mechanical allodynia in diabetic neuropathy pain rats through the activation of the TRPC6 channel. Inhibiting TRPC6 can alleviate BDNF-induced mechanical allodynia, offering a potential novel strategy for the management of diabetic neuropathy pain.
Review
Biochemistry & Molecular Biology
Omar Mahmoud, Georgia Biazus Soares, Gil Yosipovitch
Summary: Transient Receptor Potential (TRP) channels, found abundantly in the skin, play a crucial role in the sensory pathways of itch, pain, and inflammation. This review article explores the complex physiology of different TRP channels and their involvement in modulating itch sensation and the pathophysiology of acute and chronic itch conditions. The article also highlights emerging small molecule and topical TRP channel agents as potential anti-pruritic treatments, with some advancing into clinical trials.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Oxana Yu Kytikova, Tatyana P. Novgorodtseva, Yulia K. Denisenko, Denis E. Naumov, Tatyana A. Gvozdenko, Juliy M. Perelman
Summary: Asthma is a chronic disease with a complex etiology, influenced by both natural-climatic and anthropogenic factors. Studies have shown that temperature plays a significant role in airway inflammation, and thermosensory TRP channels are crucial in the pathogenesis of asthma. New treatment methods for asthma exacerbations caused by temperature and humidity should focus on regulating channel activity.
Article
Chemistry, Medicinal
Zhuang Zhang, Lili Chen, Hongtao Tian, Mengru Liu, Shan Jiang, Jianhua Shen, Kai Wang, Zhengyu Cao
Summary: The synthesis and biological evaluation of a series of pyrroledione TRPC5 inhibitors has led to the discovery of compound 16g with subtype selectivity, showing improved inhibition of TRPC5 and enhanced protective effect against PS-induced podocyte injury in vitro. Compound 16g also demonstrated no cell death in primary cultured hepatocytes and immortalized podocytes in a preliminary toxicity assessment, suggesting its potential as a potent and safe inhibitor for studying the function of TRPC5.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Cell Biology
Christine Haewon Park, Jinsung Kim, Jung Eun Lee, Misun Kwak, Insuk So
Summary: This study focuses on the pore region of TRPC1 and TRPC4 as a determinant of the characteristics of a heteromeric TRPC1/4 channel. Mutants and chimeras were used to investigate the effects of changes in the pore region on calcium permeability and current-voltage curve.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2023)
Article
Oncology
Florian Lassig, Anja Klann, Sander Bekeschus, Uwe Lendeckel, Carmen Wolke
Summary: The study found that Mas-dependent alterations in osteosarcoma cell line proliferation were not mediated by changes in TRPC subtype gene expression. The data shows that the signaling pathways examined can regulate the expression of TRPCs at the mRNA level. Targeting TRPC subtypes through specific signaling pathways may offer potential for improving osteosarcoma treatment.
Review
Oncology
Haoran Zha, Ying Jiang, Xi Wang, Jin Shang, Ning Wang, Lei Yu, Wei Zhao, Zhihua Li, Juan An, Xiaochun Zhang, Huoming Chen, Bo Zhu, Zhaoxia Li
Summary: PD-1-based immunotherapy has been a game-changer in cancer treatment, but not all patients benefit from it and some may even experience hyperprogressive disease. In addition to CD8 T cells and conventional T cells, other cell types like B cells, regulatory T cells, natural killer cells, dendritic cells, tumor-associated macrophages, and cancer cells also express PD-1, contributing to the response to PD-1 blockade therapy. Further research is exploring the role of non-canonical PD-1 signaling in different cell types and how this knowledge can enhance the effectiveness of PD-1 blockade immunotherapy.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2021)
Article
Pharmacology & Pharmacy
Xiao-Yu Cheng, Shu-Fang Li, Yong Chen, Ying-Jie Zhao, Wei Hu, Chao Lu, Ren-Peng Zhou
Summary: TRPM7 is a channel protein located on the cell membrane that regulates the balance of intracellular Mg2+. It plays an important role in cell proliferation, adhesion, migration, and is directly related to disease occurrence and development.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Applied
Rene Lebl, Yutong Zhu, Derrick Ng, Christian H. Hornung, David Cantillo, C. Oliver Kappe
Summary: The novel catalytic static mixers with rectangular cross-section coated with Pd/Al2O3 have shown excellent catalytic performance for continuous flow hydrogenation of nitroaromatics. The heterogeneous catalyst is highly stable, with essentially no leaching of Pd or Al observed after long periods of activity. The process has been successfully showcased for the synthesis of the key intermediate of the medicine tizanidine.
Review
Neurosciences
Matthias Sallinger, Herwig Grabmayr, Christina Humer, Daniel Bonhenry, Christoph Romanin, Rainer Schindl, Isabella Derler
Summary: STIM proteins are ER-transmembrane proteins that act as Ca2+ sensors and interact with Orai proteins to activate the CRAC channel. The activation of STIM requires the depletion of ER Ca2+ store, and the conformational dynamics of STIM are associated with disease.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Automation & Control Systems
Ismael Castillo, Jakob Rehrl, Peter Sagmeister, Rene Lebl, Julia Kruisz, Selma Celikovic, Martin Sipek, Dirk Kirschneck, Martin Horn, Stephan Sacher, David Cantillo, Jason D. Williams, Johannes G. Khinast, Oliver Kappe
Summary: This paper presents the application of Data Driven Modelling (DDM) and Non-Linear Model Predictive Control (NMPC) for the control implementation of a continuous reactor for the production of the Active Pharmaceutical Ingredient (API), Mesalazine. The contribution of this work is to present the overall control architecture, the step-by-step controller design based on DDM, i.e. Neuro-Fuzzy/Local Linear Model Tree Models (LoLiMoT) and NMPC. We demonstrate the advantages of DDM and NMPC, in the presence of non-linear, distributed parameter, multi-variable systems as a suitable, powerful and practical way to approach complex process control challenges. Compared to conventional concepts, the inherent optimization structure of NMPC allows to obtain the desired behaviour of the multi-variable non-linear plant considering the physical constraints of operation regions. The control concept has been implemented in the real system on one central computer, XamControl (Evon),1 with all measurement devices and actuators centrally interconnected. (c) 2022 Elsevier Ltd. All rights reserved.
JOURNAL OF PROCESS CONTROL
(2023)
Article
Chemistry, Applied
Kevin Simon, Desiree Znidar, Julien Boutet, Gerard Guillamot, Jean-Yves Lenoir, Doris Dallinger, C. Oliver Kappe
Summary: A proof-of-concept study for the synthesis of 1,2-difluorobenzene from 2-fluoroaniline via the Balz-Schiemann reaction using HF/pyridine as the fluorinating reagent is reported. The key to success was the photochemically induced fluorodediazoniation of the in situ-generated diazonium salt performed in a continuous flow mode. The use of a high-power 365 nm light-emitting diode improved the reaction performance and allowed the generation of 1,2-difluorobenzene within a 10 min residence time and a product selectivity of >= 95% at full conversion.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Multidisciplinary Sciences
Marco Niello, Spyridon Sideromenos, Ralph Gradisch, Ronan O'Shea, Jakob Schwazer, Julian Maier, Nina Kastner, Walter Sandtner, Kathrin Jantsch, Carl R. Lupica, Alexander F. Hoffman, Gert Lubec, Claus J. Loland, Thomas Stockner, Daniela D. Pollak, Michael H. Baumann, Harald H. Sitte
Summary: By using various in vitro, computational, and in vivo approaches, we found that the drug-binding kinetics of S-enantiomers of pyrovalerone analogs at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, the slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT can predict their more persistent in vivo effects compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT in determining the in vivo profile of effects produced by psychostimulant drugs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Ferdinand Horvath, Sascha Berlansky, Lena Maltan, Herwig Grabmayr, Marc Fahrner, Isabella Derler, Christoph Romanin, Thomas Renger, Heinrich Krobath
Summary: STIM1 is a protein located in the endoplasmic reticulum (ER) membrane that senses the concentration of calcium ions and plays a role in the activation of calcium channels. Through molecular docking simulations, a structural model of the resting state of STIM1 was established, and the binding interface was analyzed using molecular dynamics simulations. Experimental results confirmed the validity of the model and provided insights into the conformational dynamics of the resting state of STIM1.
Article
Chemistry, Multidisciplinary
Gang Fu, Juncheng Jiang, Christopher A. Hone, C. Oliver Kappe
Summary: This paper demonstrates the reliable measurement of highly exothermic, rapid reactions using a modular 3D printed continuous flow calorimeter. The influence of mixing efficiency on reaction conversion and product selectivity is investigated through computational fluid dynamics simulations. The reaction enthalpies for the synthesis of desired products are successfully deconvoluted. In addition, the exothermic characteristics of a lithium-halogen exchange and iodine quench reaction are studied.
REACTION CHEMISTRY & ENGINEERING
(2023)
Article
Chemistry, Applied
Philipp Petermeier, Christoph Kohlfuerst, Ana Torvisco, Roland C. C. Fischer, Alejandro Mata, Doris Dallinger, C. Oliver Kappe, Joerg H. H. Schrittwieser, Wolfgang Kroutil
Summary: Substituted piperidine rings are efficiently prepared with multiple stereocentres using multi-enzymatic and chemo-enzymatic methods from achiral diketoester precursors. Highly enantioselective transamination and diastereoselective reduction processes enable the synthesis of optically pure piperidines. This approach offers a more streamlined and efficient route for the synthesis of trisubstituted piperidines with potential applications in drug discovery.
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Editorial Material
Cell Biology
Isabella Derler, Christoph Romanin
Article
Biology
Zsuzsanna Gyongy, Gabor Mocsar, Eva Hegedus, Thomas Stockner, Zsuzsanna Ritter, Laszlo Homolya, Anita Schamberger, Tamas Orban, Judit Remenyik, Gergely Szakacs, Katalin Goda
Summary: This study presents methods for simultaneously investigating substrate and nucleotide binding by ABCG2 in cells. The switch from the inward-facing to the outward-facing conformation of ABCG2 is induced by nucleotide binding and facilitated by substrates, while hindered by the inhibitor Ko143. The high-to-low affinity switch of the drug binding site coincides with the transition from the inward-facing to the outward-facing conformation.
Review
Physiology
Manan Bhatt, Laure Gauthier-Manuel, Erika Lazzarin, Rocco Zerlotti, Christine Ziegler, Andre Bazzone, Thomas Stockner, Elena Bossi
Summary: γ-Aminobutyric acid (GABA) acts as the primary inhibitory neurotransmitter in the CNS, regulated by GABA transporters (GATs). Although GAT1 has been extensively studied, the roles of other GABA transporters, especially BGT-1, remain unclear. This review aims to compare GAT1 and BGT-1, leveraging the knowledge of GAT1 to shed light on the unanswered questions regarding BGT-1.
FRONTIERS IN PHYSIOLOGY
(2023)
Editorial Material
Cell Biology
Klaus Groschner
Summary: The endoplasmic reticulum (ER) is crucial for cellular calcium signaling, with IP3R channels playing a key role in regulating calcium levels. Recent research has uncovered a previously overlooked function of IP3R1 in neurons, showing its involvement in supporting STIM/Orai-mediated store-operated calcium entry (SOCE).
Article
Chemistry, Medicinal
Kornel Ozvoldik, Thomas Stockner, Elmar Krieger
Summary: The transition from 3D glasses to VR headsets in the industry has brought challenges for modelers. However, a novel software implementation using a VR headset at a desk has been introduced, providing a relaxing and immersive workplace. This software, called YASARA Model, combines VR functionality with a molecular graphics engine and offers additional features and interactive tutorials.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Multidisciplinary
Dominik Polterauer, Dominique M. Roberge, Paul Hanselmann, Ryan Littich, Christopher A. Hone, C. Oliver Kappe
Summary: This article introduces a new continuous flow method for the synthesis of sulfonyl chlorides from disulfides and thiols, using 1,3-dichloro-5,5-dimethylhydantoin (DCH) as the oxidative chlorination reagent. Under optimized conditions, sulfonyl chlorides can be synthesized at high yields, with a high space-time yield.
REACTION CHEMISTRY & ENGINEERING
(2022)
Meeting Abstract
Biophysics
Ralph Gradisch, Daniel Szollosi, Marco Niello, Harald Sitte, Thomas Stockner
BIOPHYSICAL JOURNAL
(2022)