Synergistic Network Pharmacology: Preclinical Validation and Clinical Safety in Acute Ischemic Stroke

BACKGROUND: Most human disease definitions, except for rare and communicable diseases, are based on symptoms in specific organs, not on causal molecular mechanisms. This limits treatments to imprecise symptomatic approaches with high numbers needed to treat. Systems medicine, instead, has a holistic approach and defines diseases in an organ-agnostic manner on the basis of associated risk genes, their encoded proteins, and protein-protein interactions. Dysregulation of such disease modules is best corrected by multitarget, synergistic network pharmacology. Here we test this principle in acute ischemic stroke, a highly unmet medical indication without any approved neuroprotective drug so far. METHODS: We extend 3 validated risk genes, neuronal nitric oxide synthase (NOS1), NADPH oxidase 5 (NOX5), and soluble guanylate cyclase (sGC), to a single disease module. For preclinical validation, we used C57/Bl6 mice and humanized NOX5-knock-in mice because NOX5 is not present in the mouse genome despite playing a key role in early stroke. Because up to 70% of patients with stroke have diabetes or prediabetes as an aggravating comorbidity, we also induced diabetes in these mice to model the increased clinical risk for hemorrhagic transformation. RESULTS: We found that a triple-drug combination of a NOX inhibitor, a nitric oxide synthase inhibitor, and an sGC activator reduced infarct size and, in diabetic animals, also prevented hemorrhagic transformation. Reducing each individual compound dose to subthreshold levels still resulted in full protection when combined, typical for supra-additive network pharmacology. To examine clinical safety, 3 drugs, either marketed for sGC or repurposed for nitric oxide synthase and NADPH oxidase, were administered to healthy volunteers in a phase I trial. CONCLUSIONS: Our data establish that a mechanism-based network pharmacology approach is effective and clinically safe, warranting a currently ongoing first-in-class neuroprotective phase II interventional trial. REGISTRATION: URL: https://clinicaltrials.gov/study/NCT05762146?term=repo-stroke&rank=1; Unique Identifier: NCT05762146

Inducible nitric oxide synthase (iNOS) expression may predict distant metastasis in human melanoma

Expression of inducible nitric oxide synthase (iNOS) and its cellular localization was investigated in subcutaneous or lymph node metastases of human melanoma. Immunohistochemistry revealed that iNOS expression was limited to melanoma cells. In samples of patients without distant metastases, the number of iNOS+ tumour cells/total tumour cells was 55% ± 17% (n = 12) compared with 9% ± 8% when distant metastases of lung, liver or brain occurred within an observation period of 3 years (n = 10) (P < 0.001). Western blotting confirmed the expression of iNOS protein in select cases. Notably, iNOS is expressed in regional melanoma metastases and its expression is inversely related to the tumour's metastatic potential. Thus, iNOS expression may have predictive value for the development of distant metastases of human melanoma. © 1999 Cancer Research Campaig

The Concise Guide to PHARMACOLOGY 2023/24: Catalytic receptors.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Community effort endorsing multiscale modelling, multiscale data science and multiscale computing for systems medicine

© 2017 The Author 2017. Published by Oxford University Press. Systems medicine holds many promises, but has so far provided only a limited number of proofs of principle. To address this road block, possible barriers and challenges of translating systems medicine into clinical practice need to be identified and addressed. The members of the European Cooperation in Science and Technology COST) Action CA15120 Open Multiscale Systems Medicine OpenMultiMed) wish to engage the scientific community of systems medicine and multiscale modelling, data science and computing, to provide their feedback in a structured manner. This will result in follow-up white papers and open access resources to accelerate the clinical translation of systems medicine.Austrian Science Fund: Special Research Program SFB-F54. The European Cooperation in Science and Technology (COST) Action CA15120 OpenMultiMed (http://openmultimed.net)

THE CONCISE GUIDE TO PHARMACOLOGY 2019/20 : G protein- coupled receptors

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.Peer reviewe