Glycine transporter inhibitors

Interneurons operating with glycine neurotransmitter are involved in the regulation of pain transmission in the dorsal horn of the spinal cord. In addition to interneurons, glycine release also occurs from glial cells neighboring glutamatergic synapses in the spinal cord. Neuronal and glial release of glycine is controlled by glycine transporters (GlyTs). Inhibitors of the two isoforms of GlyTs, the astrocytic type-1 (GlyT-1) and the neuronal type-2 (GlyT-2), decrease pain sensation evoked by injuries of peripheral sensory neurons or inflammation. The function of dorsal horn glycinergic interneurons has been suggested to be reduced in neuropathic pain, which can be reversed by GlyT-2 inhibitors (Org-25543, ALX1393). Several lines of evidence also support that peripheral nerve damage or inflammation may shift glutamatergic neurochemical transmission from N-methyl-D aspartate (NMDA) NR1/NR2A receptor- to NR1/NR2B receptor-mediated events (subunit switch). This pathological overactivation of NR1/NR2B receptors can be reduced by GlyT-1 inhibitors (NFPS, Org-25935), which decrease excessive glycine release from astroglial cells or by selective antagonists of NR2B subunits (ifenprodil, Ro 25-6981). Although several experiments suggest that GlyT inhibitors may represent a novel strategy in the control of neuropathic pain, proving this concept in human beings is hampered by lack of clinically applicable GlyT inhibitors. We also suggest that drugs inhibiting both GlyT-1 and GlyT-2 non-selectively and reversibly, may favorably target neuropathic pain. In this paper we overview inhibitors of the two isoforms of GlyTs as well as the effects of these drugs in experimental models of neuropathic pain. In addition, the possible mechanisms of action of the GlyT inhibitors, i.e. how they affect the neurochemical and pain transmission in the spinal cord, are also discussed. The growing evidence for the possible therapeutic intervention of neuropathic pain by GlyT inhibitors further urges development of drugable compounds, which may beneficially restore impaired pain transmission in various neuropathic conditions

Modeling in systems biology: Causal understanding before prediction?

Babur et al. (2021) developed the CausalPath tool to infer causal signaling interactions in high-throughput proteomics data that may foster mechanical understanding from large-scale biological datasets

Arteria centralis retinae elzáródás thrombolysiskezelése és multidiszciplináris ellátása a hagyományos szemészeti kezelési formákkal összehasonlítva = Thrombolysis treatment and multidisciplinary management of central retinal artery occlusion in comparison with traditional ophthalmological treatment options

Háttér és cél – Az arteria centralis retinae okklúzió (ACRO) eddigi konzervatív terápiái limitált hatékonyságúak, szemészeti osztályokon történtek, ahogyan az egységes protokoll nélküli etiológiai vizsgálatok is. Pedig az ACRO a központi idegrendszeri ischaemiás stroke analógiájának tekinthető, így a szisztémás thrombolysis és a multidiszciplináris ellátás hasonlóan hatékony lehet. Emiatt 2022 májusa óta a Semmelweis Egyetemen klinikai vizsgálat keretében a 4,5 órán belül diagnosztizált ACRO thrombolysiskezelését és etiológiai vizsgálatait végezzük egységes protokoll alapján. Vizsgálatunk célja a szemészeti, nem protokoll szerinti, és a multidiszciplináris, protokoll szerinti ACRO-ellátás összehasonlítása. Módszerek – Áttekintettük a 2013 és 2022 között a Szemészeti Klinikán ACRO-val konzervatívan és 6 órán belül paracentesissel is kezelt betegek látásélesség-változását, fellelhető neurológiai és cardiovascularis vizsgálatainak eredményeit, valamint a thrombolysisprojekt keretében ellátott betegeket. Eredmények – A 78 nem protokoll szerinti ellátásban részesülő betegnél látásjavulást természetes lefolyás esetén 37%, konzervatív kezelés mellett 47%, paracentesissel 47%-nál láttunk. Szignifikáns carotisstenosis négy, carotisdissectio egy, cardialis emboliaforrás hat, óriássejtes arteritis egy esetben igazolódott; endarterectomián két beteg esett át. A protokoll szerinti klinikai vizsgálatba négy, időablakon belüli betegből három egyezett bele, náluk thrombolysis történt. Két betegnek javult a visusa, két betegnél szignifikáns carotisstenosis igazolódott, és endarterectomián estek át, egy betegnél novum pitvarfibrilláció miatt antikoagulálást kezdtünk. Következtetés – A terápiás időablakon belül jelentkező ACRO-betegek ritkák, a thrombolysis hatásosságának megítéléséhez nagyobb betegszám szükséges. Az egységes vizsgálati protokoll azonban egyértelműen elősegíti az etiológiai diagnózist, így a további, akár súlyosabb formában jelentkező thromboemboliás szövődmények megelőzését. | Background and purpose – The manage- ment of central retinal artery occlusion (CRAO) has long been conservative therapy with limited efficacy carried out in ophthal- mology departments together with etiolo- gi cal investigations lacking a standardised protocol. However, CRAO is analogous to ischemic central nervous system stroke and is associated with increased stroke risk, thus, systemic thrombolysis treatment and multi- disciplinary management can be beneficial. Since May 2022, at Semmelweis University CRAO patients diagnosed within 4.5 hours are given intravenous thrombolysis therapy and undergo etiologic workup based on current stroke protocols. Here we report our experience with the multidisciplinary, protocol-based management of CRAO in comparison with former non-protocol based ophthalmological conservative treatment. Methods – We reviewed CRAO patients’ data treated conservatively and with para- centesis within 6 hours at the Department of Ophthalmology between 2013 and 2022 including changes in visual acuity, neurolo- gical and cardiovascular findings compared to those in the thrombolysis project. Results – Of the 78 patients receiving non- protocol care, visual improvement was seen n 37% with natural course, 47% with con- servative treatment and 47% with paracen- tesis. Four patients had significant carotid stenosis (2 underwent endarterectomy), 1 carotid dissection, 6 cardioembolism and 1 giant cell arteritis. Of the 4 patients within 4,5 hours, 3 gave their consent to the clinical trial and were treated with thrombolysis and underwent a full etiological assessment. 2 patients had improved visual acuity, 2 patients had significant carotid stenosis and underwent endarterectomy, 1 patient was started on anticoagulation for newly diagnosed atrial fibrillation. Conclusion – CRAO patients presenting within 4,5 hours are rare and more patients are needed in our study to establish the efficacy of thrombolysis. However uniform protocollized evaluation helps identifying embolic sources thus, avoiding further and potentially more serious thromboembolic events

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity.

Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity-and not inverse similarity-between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect

An Unexpected Enzyme in Vascular Smooth Muscle Cells: Angiotensin II Upregulates Cholesterol-25-Hydroxylase Gene Expression

Angiotensin II (AngII) is a vasoactive peptide hormone, which, under pathological conditions, contributes to the development of cardiovascular diseases. Oxysterols, including 25-hydroxycholesterol (25-HC), the product of cholesterol-25-hydroxylase (CH25H), also have detrimental effects on vascular health by affecting vascular smooth muscle cells (VSMCs). We investigated AngII-induced gene expression changes in VSMCs to explore whether AngII stimulus and 25-HC production have a connection in the vasculature. RNA-sequencing revealed that Ch25h is significantly upregulated in response to AngII stimulus. The Ch25h mRNA levels were elevated robustly (~50-fold) 1 h after AngII (100 nM) stimulation compared to baseline levels. Using inhibitors, we specified that the AngII-induced Ch25h upregulation is type 1 angiotensin II receptor- and Gq/11 activity-dependent. Furthermore, p38 MAPK has a crucial role in the upregulation of Ch25h. We performed LC-MS/MS to identify 25-HC in the supernatant of AngII-stimulated VSMCs. In the supernatants, 25-HC concentration peaked 4 h after AngII stimulation. Our findings provide insight into the pathways mediating AngII-induced Ch25h upregulation. Our study elucidates a connection between AngII stimulus and 25-HC production in primary rat VSMCs. These results potentially lead to the identification and understanding of new mechanisms in the pathogenesis of vascular impairments