British Journal of Pharmacology最新文献

{"title":"Synthetic microneurotrophins: Neurotrophin receptors for therapeutics of neurodegenerative diseases.","authors":"Ioanna Zota, Theodora Calogeropoulou, Konstantina Chanoumidou, Ioannis Charalampopoulos, Achille Gravanis","doi":"10.1111/bph.70143","DOIUrl":"https://doi.org/10.1111/bph.70143","url":null,"abstract":"<p><p>Neurodegenerative disorders are characterised by the chronic progressive degeneration of specific neuronal subtypes, neuroinflammation, myelin damage and synaptic loss. Despite their growing incidence, advancements in effective treatments remain limited, because of lack of knowledge for the aetiology of the diverse pathophysiology to design systematic therapies. Several studies highlight the role of neurotrophic factors (NTFs) as potential neuroprotective, regenerative therapies for these disorders. Although NTFs hold protective and regenerative potential for chronic neuroinflammatory and neurodegenerative conditions, major hurdles impair their clinical use, such as optimising the dosage of NTFs, minimising the invasiveness of delivery methods, overcoming blood-brain-barrier (BBB) impermeability and managing side effects. In the last two decades our group have synthesised and screened a large chemical library of steroidal analogues of dehydroepiandrosterone (DHEA), an endogenous steroid hormone, for their ability to mimic neurotrophin neuroprotective and neurogenic actions. Interestingly, DHEA was shown to interact with all neurotrophin receptors, acting most probably as an ancestral neurotrophin early in evolution. However, its chronic pharmacological use is questioned by its action as a major precursor of steroidogenesis. This review highlights the findings of numerous preclinical studies on these synthetic, non-toxic, BBB permeable DHEA derivatives, named microneurotrophins (MNTs), deprived of endocrine actions, activators of specific neurotrophin receptors. The multimodal actions of MNTs against neuronal death and activation of microglia, in addition to their beneficial effects in synaptogenesis and neurogenesis, place them as interesting lead molecules in the armamentarium of therapeutics for neurodegeneration.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoflurane and urethane impact neuronal and astroglial metabolic activity differentially in mouse brain: An ex vivo ¹H-[¹³C]-NMR study.","authors":"Sreemantula Arun Kumar, Akila Ramesh, Pooja Gautam, Anant Bahadur Patel","doi":"10.1111/bph.70113","DOIUrl":"https://doi.org/10.1111/bph.70113","url":null,"abstract":"<p><strong>Background and purpose: </strong>Isoflurane and urethane are among the most routinely used anaesthetics to immobilise rodents in functional studies. However, the quantitative significance of their impacts on neuronal and astroglial activity is not very clear. This study evaluated the impacts of isoflurane and urethane on the metabolic activity of glutamatergic neurons, GABAergic neurons and astrocytes in different brain regions.</p><p><strong>Experimental approach: </strong>Male C57BL/6 mice were anaesthetised with either isoflurane (1.5%) or urethane (1.5 g kg^-1, intraperitoneal), and administered [1,6-¹³C₂]glucose or [2-¹³C]acetate intravenously for 10 or 15 min, respectively. The brain metabolism was arrested using Focussed Beam Microwave Irradiation, and the ¹³C labelling of neurometabolites in the brain tissue extracts was measured ex vivo using ¹H-[¹³C]-nuclear magnetic resonance (NMR) spectroscopy.</p><p><strong>Results: </strong>The levels of aspartate and succinate were decreased, while alanine increased in the studied brain regions in mice exposed to isoflurane compared to awake mice. The labelling of Glu_C4/C3, GABA_C2 and Gln_C4 from [2-¹³C]acetate was decreased in the isoflurane group when compared with awake, suggesting that isoflurane suppresses the astroglial metabolic activity, particularly in the subcortical region. There was a severe reduction in the ¹³C labelling of brain amino acids from [1,6-¹³C₂]glucose in all the brain regions in isoflurane and urethane groups of mice, indicating a severe impact of both anaesthetics on the metabolic activity of glutamatergic and GABAergic neurons.</p><p><strong>Conclusions and implications: </strong>These findings demonstrate that isoflurane and urethane differentially reduce excitatory and inhibitory synaptic transmissions in the brain. Notably, isoflurane shifts cerebral metabolism towards anaerobic respiration.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fast-dissociating D₂ antagonist antipsychotic JNJ-37822681 is a neuronal Kv7 channel opener: Potential repurposing for epilepsy treatment.","authors":"Lidia Carotenuto, Oliver Keminer, Giusy Carleo, Andrea Zaliani, Antonio Leo, Rita Citraro, Giovambattista De Sarro, Nina Dirkx, Marcus Kaji, Sarah Weckhuysen, Jeanette Reinshagen, Vincenzo Barrese, Natascia Guida, Carmine Ostacolo, Francesco Miceli, Philip Gribbon, Maurizio Taglialatela","doi":"10.1111/bph.70119","DOIUrl":"https://doi.org/10.1111/bph.70119","url":null,"abstract":"<p><strong>Background and purpose: </strong>Pharmacological activation of neuronal M-current mediated by Kv7 (Kv7.2-5) potassium channels is a validated mechanism for epilepsy treatment. However, since the market withdrawal of the prototype Kv7 activator retigabine, no Kv7 activator is clinically available for this condition. The object was to identify, characterise and validate new neuronal Kv7 channel activators for epilepsy treatment.</p><p><strong>Experimental approach: </strong>A fluorescence-based high-throughput assay was optimised in cells stably expressing Kv7 channels to screen two repurposing libraries including >8000 compounds. Whole-cell patch clamp, in silico docking, mutagenesis and multielectrode array recordings in human induced-pluripotent stem cell (hiPSCs)-derived cortical-like glutamatergic neurons (iNeurons) were used to evaluate compound(s) potency and efficacy, binding site, and effects on neuronal activity, respectively. Finally, anticonvulsant activity was assessed in two acute seizure models in male mice.</p><p><strong>Key results: </strong>JNJ-37822681, a fast-dissociating D₂ receptor antagonist in clinical development as antipsychotic, enhanced Kv7.2-5 currents with potency and efficacy largely comparable to retigabine. In Kv7.2 subunits, JNJ-37822681 binding site largely overlapped that for retigabine. In iNeurons, JNJ-37822681 enhanced the M-current, hyperpolarised the resting membrane potential and reduced spontaneous action potential firing. These effects were blocked by the Kv7 antagonist, XE-991, and were not reproduced by the D₂ antagonist (-)-sulpiride. Finally, JNJ-37822681 showed anticonvulsant activity in two well-validated mouse models of acute seizures.</p><p><strong>Conclusions and implications: </strong>Our study reveals that JNJ-37822681, which lacks retigabine's potential safety issues due to chemical liability and is already confirmed as safe for human use, represents a potential treatment of Kv7-related neuronal hyperexcitability disorders.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based discovery of thiamine uptake inhibitors.","authors":"Florian Gabriel, Björn Windshügel, Christian Löw","doi":"10.1111/bph.70133","DOIUrl":"https://doi.org/10.1111/bph.70133","url":null,"abstract":"<p><strong>Background and purpose: </strong>Thiamine (vitamin B₁) is an essential coenzyme and catalyses various reactions in central metabolic pathways. Since mammals have lost the ability to synthesise thiamine de novo, this micronutrient has to be imported via the high affinity solute carriers SLC19A2 and A3 across the plasma membrane. Perturbations of these transport systems have severe effects on human health. Recent structural work on SLC19A2 and A3 have provided molecular insights into substrate and drug recognition and conformational changes during transport. Based on the analysis of the available SLC19A3 structures, we hypothesise that the binding site is rather promiscuous, allowing different small molecules to interact and potentially inhibit this transporter.</p><p><strong>Experimental approach: </strong>We employed a computational approach, by which 538 approved and investigational drugs were docked into an ensemble of SLC19A3 cryo-EM structures, followed by experimental binding studies, transport inhibition assays, and structural validation.</p><p><strong>Key results: </strong>Eight novel compounds were identified that bind and inhibit SLC19A3. To visualise such a new drug interaction, we determined the cryo-EM structure of SLC19A3 bound to domperidone, a dopamine D₂ receptor antagonist used for the treatment of nausea and gastrointestinal disorders. Our computational work together with biochemical and cellular transport assays expands the understanding of SLC19A3-drug interactions, highlights the power of virtual screening approaches using structural ensembles, and provides a three-dimensional pharmacophore model for SLC19A3 inhibitors.</p><p><strong>Conclusion and implications: </strong>These findings offer a basis for addressing drug-induced thiamine deficiencies and pre approach can be used to optimise pharmacological strategies involving SLC19A3-interacting compounds in the future.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological targeting of large tumor suppressor kinases (LATS) 1 and 2 augments tissue repair and regeneration.","authors":"Chen Xiao, Zhenhua Wu, Liuqi Liao, Chao Shi, Huan Gao, Ting Zhang, Qinghua Chen, Yongqiang Hou, Cai-Hong Yun, Dongxue Su, Dawang Zhou, Xianming Deng, Lanfen Chen","doi":"10.1111/bph.70137","DOIUrl":"https://doi.org/10.1111/bph.70137","url":null,"abstract":"<p><strong>Background and purpose: </strong>Large tumor suppressor kinases (LATS1 and 2) are core kinases of the Hippo signalling pathway, directly phosphorylate and inactivate the transcriptional coactivator Yes-associated protein 1 (YAP), playing a pivotal role in cell self-renewal and tissue regeneration. Hippo signalling inhibitors are urgently needed, both as tools for pharmacological studies of the Hippo pathway and as leads for developing novel, molecularly targeted drugs for the treatment of tissue injury and regeneration.</p><p><strong>Experimental approach: </strong>An enzyme linked immunosorbent assay (ELISA)-based in vitro high-throughput biochemical assay was used to the identification of a potent and reversible LATS1/2 inhibitor, N-(2-chloro-6-fluorobenzyl)-5-(1H-pyrrolo[2,3-b] pyridin-3-yl) furan-3-carboxamide (named as LPi-1). The regulation of LPi-1 on the activity of LATS1/2 kinases and YAP was evaluated both in vitro and in vivo. The murine models, including partial hepatectomy, paracetamol (acetaminophen/APAP)-induced liver hepatotoxicity and chemically induced colitis, were established to investigate the effect of LPi-1 on tissue repair and regeneration after injuries.</p><p><strong>Key results: </strong>LPi-1 effectively inhibited the activity of LATS1/2 kinases, thereby facilitating YAP activation to enhance the proliferation of hepatocytes in vitro. Moreover, LPi-1 was able to augment intestinal repair in mice following dextran sulphate sodium salt (DSS) treatment, as well as liver repair and regeneration in mice subjected to two-thirds partial hepatectomy or APAP-induced liver injury.</p><p><strong>Conclusions and implications: </strong>In conclusion, LPi-1 can serve as a valuable tool compound for exploring diverse biological functions associated with LATS1/2 kinases, as well as a promising lead compound for developing targeted therapeutic strategies aimed at enhancing tissue repair and regeneration.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Niclosamide prodrug enhances oral bioavailability and efficacy against hepatocellular carcinoma by targeting vasorin-TGFβ signalling.","authors":"Mingdian Tan, Wei Ye, Yi Liu, Xiaowu Chen, Lakshmi Huttad, Mei-Sze Chua, Samuel So","doi":"10.1111/bph.70126","DOIUrl":"https://doi.org/10.1111/bph.70126","url":null,"abstract":"<p><strong>Background and purpose: </strong>Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, has limited treatment options and high mortality rate. We previously used a bioinformatics approach to identify niclosamide (NIC) as a promising repurposed drug candidate for HCC. However, its poor water solubility and low bioavailability limit its clinical efficacy. It's mechanisms of action are not yet fully understood.</p><p><strong>Experimental approach: </strong>We designed a water-soluble NIC prodrug (NIC-PS) and evaluated its efficacy (as single agent, or in combination with sorafenib or anti-PD-L1) and mechanisms using cell-based functional assays and HCC patient-derived xenograft (PDX) mouse models. We established vasorin knockout mouse tumour models and used RNA-seq to investigate the role of vasorin in mediating NIC-PS function. Western blotting and real-time PCR were used to validate the RNA-seq data and the biological effects of NIC-PS and vasorin.</p><p><strong>Key results: </strong>NIC-PS exhibited a 10-fold increase in oral bioavailability and > 75% reduction in tumour volume in HCC PDX models. NIC binds to vasorin, and both NIC and NIC-PS suppressed vasorin expression, leading to suppression of TGFβ signalling and SMAD2/3 phosphorylation. NIC-PS enhanced the sensitivity of HCC cells and PDX to treatment with sorafenib or anti-PD-L1. Vasorin knockout results in similar effects as NIC-PS, suggesting that it partially mediates the actions of NIC-PS.</p><p><strong>Conclusion and implications: </strong>NIC-PS demonstrated improved bioavailability and antitumour efficacy compared with NIC and a potential for combination therapy with standard of care agents in HCC treatment. We also revealed its novel mechanism of action in targeting vasorin.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semax peptide targets the μ opioid receptor gene Oprm1 to promote deubiquitination and functional recovery after spinal cord injury in female mice.","authors":"Rongjie Liu, Yituo Chen, Haosheng Huang, Xiang Li, Junlei Lv, Liting Jiang, Hongyi Jiang, Chenyu Wu, Weikai Chen, Hongwei Xu, Zhefan Zhu, Haoxu Cai, Jian Xiao, Lihui Yin, Wenfei Ni","doi":"10.1111/bph.70122","DOIUrl":"https://doi.org/10.1111/bph.70122","url":null,"abstract":"<p><strong>Background and purpose: </strong>Lysosomal membrane permeabilization (LMP) is exacerbated following spinal cord injury (SCI), leading to increased neuronal cell death. Ubiquitination may affect LMP by regulating the stability and functionality of lysosomal membranes. Semax, a synthetic heptapeptide, comprising the ACTH (4-7) fragment and a C-terminal Pro-Gly-Pro tripeptide, exhibits neuroprotective properties and improves cognitive function. Given the key roles of LMP and ubiquitination in SCI pathophysiology, this study investigated how Semax could modulate these pathways to affect functional recovery following SCI.</p><p><strong>Experimental approach: </strong>An SCI mouse model was generated by impacting the spinal cord of female C57BL/6 mice at T9-T10. Functional recovery in SCI mice was evaluated using histochemical methods, along with footprint analysis, Basso scores and inclined plane tests. Marker levels and distributions in the SCI model and in the PC12 cell neuroinflammation model were analysed using immunofluorescence, Western blot, RT-qPCR and transmission electron microscopy. RNA sequencing, network pharmacology and molecular docking were used to identify possible molecular targets of Semax.</p><p><strong>Key results: </strong>Semax improved SCI functional recovery and inhibited LMP-related pyroptosis in SCI mice and neuroinflammation models, by decreasing oxidative stress. RNA-seq and other analyses found that Semax regulated the ubiquitin specific protease USP18. USP18 knockdown confirmed Semax's role in SCI recovery. Network pharmacology and docking revealed the μ-opioid receptor as a Semax target.</p><p><strong>Conclusion and implications: </strong>Semax promoted SCI functional recovery by targeting μ-opioid receptors, which regulated USP18 and, subsequently, deubiquitination of the fat mass and obesity-associated protein (FTO), suggesting its potential for SCI treatment.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-nociceptive action of leonurine through TRPA1 and TRPV4 channels modulation.","authors":"Matilde Marini, Lorenzo Landini, Elisabetta Coppi, Martina Tesi, Elisa Bellantoni, Martina Chieca, Emma Beatrice Croce, Lorenzo Bonacchi, Giulia Brancolini, Piero Bruschi, Daniel Souza Monteiro de Araújo, Gaetano De Siena, Alexandra Dimitrova, Alessandra Mastricci, Henrique Rocha Mendonça, Irene Scuffi, Martina Venturini, Luiza Dos Santos Heringer, Fabio Vaiano, Romina Nassini, Francesco De Logu","doi":"10.1111/bph.70135","DOIUrl":"https://doi.org/10.1111/bph.70135","url":null,"abstract":"<p><strong>Background and purpose: </strong>Leonurine, a pseudoalkaloid derived from Leonotis leonurus, has been traditionally used in herbal medicine to alleviate conditions such as headaches and abdominal discomfort. Its therapeutic effects are often attributed to potential antioxidant properties; however, the precise molecular mechanisms remain poorly understood. Transient Receptor Potential (TRP) channels, particularly TRPA1 and TRPV4, serve as critical sensors of reactive oxygen species (ROS). Persistent ROS elevation can contribute to pain by activating these channels.</p><p><strong>Experimental approach: </strong>Here, we examined the antinociceptive properties of leonurine and its modulatory effects on TRPA1 and TRPV4 channels after stimulation with selective (allyl isothiocyanate (AITC) and GSK1016790A, respectively) or non-selective (hydrogen peroxide, H₂O₂) agonists. Employing human and murine cell lines expressing TRPA1 and TRPV4, and mouse primary sensory neurons from dorsal root ganglia (DRG), we observed that leonurine elicited a selective, concentration-dependent increase in intracellular calcium levels, followed by desensitisation of both channels. Notably, TRPA1 and TRPV4 have been implicated in the development and maintenance of mechanical allodynia within models of chemotherapy-induced peripheral neuropathy (CIPN). We used a thalidomide CIPN model to assess the efficacy of leonurine to reduce TRPA1- and TRPV4-dependent mechanical allodynia.</p><p><strong>Key results: </strong>Our findings indicate that repeated, but not acute, administration of leonurine significantly reduced thalidomide-induced mechanical allodynia, highlighting the crucial role of TRPA1 and TRPV4 desensitisation in pain modulation.</p><p><strong>Conclusions and implications: </strong>These results position leonurine as a promising candidate for pain management, warranting further investigation into long-term therapeutic strategies and potential clinical applications.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of 3-mercaptopyruvate sulfurtransferase (3-MST) inhibitors on contractile responses in porcine coronary artery.","authors":"Maha Almaheize, Sahar Alharthi, Patricia Hemp, Jennifer Mattos, Marcus van Leer, Michael Garle, Stephen Alexander, Richard Roberts","doi":"10.1111/bph.70141","DOIUrl":"https://doi.org/10.1111/bph.70141","url":null,"abstract":"<p><strong>Background and purpose: </strong>Hydrogen sulphide (H₂S) is synthesised endogenously through cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although exogenous H₂S is known to produce vasodilatation, the vascular effect of H₂S produced through 3-MST is unknown. In this study, we demonstrate the effect of a novel inhibitor of 3-MST, namely DPHE, and determined the effect of this compound on contractile responses in porcine coronary artery.</p><p><strong>Experimental approach: </strong>Synthesis of H₂S through 3-MST and CBS/CSE was determined in rat liver cytosol. Effects of 3-MST inhibitors DPHE, 3-PAB, or I3MT-3, or CBS/CSE inhibitors AOAA and propargylglycine (PPG) on contractile responses in porcine coronary arteries were determined using isolated tissue baths.</p><p><strong>Key results: </strong>DPHE inhibited the production of H₂S from 3-mercaptopyruvate (IC₅₀ ~ 8 μM). The 3-MST inhibitors DPHE, I3MT-3 and 3-PAB all inhibited contractions to U46619 in porcine coronary artery segments through an endothelium-independent mechanism. DPHE and I3MT-3 reduced the U46619 contractions in the absence of extracellular calcium and inhibited the contraction to the L-type calcium channel opener BAY K8644. The combination of AOAA (100 μM) and PPG (10 μM) had no effect on the U46619 contractions. The inhibitory effect of the 3-MST inhibitors does not appear to involve Rho kinase, ERK-MAP kinase or the mitochondrial electron transport chain.</p><p><strong>Conclusions and implications: </strong>Inhibition of 3-MST in coronary arteries leads to an inhibition of both calcium-dependent and calcium-independent contractions, whereas CBS/CSE inhibitors had no effect on receptor-mediated contractions. These data suggest that 3-MST, not CBS/CSE, regulates vascular tone in porcine coronary artery.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-canonical PKG1 regulation in cardiovascular health and disease.","authors":"Jie Su, Joseph Robert Burgoyne","doi":"10.1111/bph.70148","DOIUrl":"https://doi.org/10.1111/bph.70148","url":null,"abstract":"<p><p>It is well established that the cyclic GMP-dependent protein kinase I (PKG1) is canonically activated by cyclic guanosine monophosphate (cGMP), enabling its regulation of vascular tone, cardiac function and smooth muscle homeostasis. However, diverse non-canonical stimuli of PKG1 have also been identified. This includes oxidants, the immune-derived cyclic nucleotide 2'3'-cyclic-GMP-AMP (cGAMP), cross-activation by cyclic adenosine 3',5'-monophosphate (cAMP) and small molecular activators. These alternative regulatory mechanisms allow fine tuning of PKG1 activity and enable the regulation of diverse cellular processes. Non-canonical activation of PKG1 plays a central role in maintaining normal cardiovascular function where oxidant-dependent mechanisms regulate blood pressure and cardiac diastolic relaxation. In addition, in situations where nitric oxide (NO) bioavailability is compromised because of endothelial dysfunction, oxidative activation can provide an alternative mechanism to maintain vascular homeostasis. Conversely in sepsis, excessive activation of PKG1 through direct oxidation or immune-derived cGAMP can contribute to hypotension and tissue injury. Thus, non-canonical modes of PKG1 activation play diverse roles which, depending on the context, can contribute to cardiovascular health or disease progression. Given its growing implications, targeting non-canonical PKG1 activation could offer promising new therapeutic strategies for cardiovascular diseases. However, achieving this requires a deeper understanding of how these alternate mechanisms influence cardiovascular health and pathology. By broadening our perspective on PKG1 regulation, this review aims to highlight new opportunities for the development of innovative cardiovascular therapies that extend beyond the canonical NO-cGMP pathway.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}