British Journal of Pharmacology最新文献

Background and purpose: The intestine plays a key role in the initiation of sepsis. The gut barrier impedes the translocation of commensal bacteria to the liver in sepsis. Previous studies have reported that angiotensin-(1-7) [Ang-(1-7)] attenuated sepsis-induced organ injury and mortality. However, its role in sepsis-induced intestinal barrier dysfunction remains unclear. Here we have investigated therapeutic effects of Ang-(1-7) on the intestinal barrier dysfunction and dysbiosis in a murine model of sepsis.

Experimental approach: We used a model of sepsis in C57BL/6 mice with caecal ligation and puncture (CLP), to assess mortality and histological and biochemical changes in the gut and liver tissues. Faecal microbiota transplantation (FMT) was used to assess the role of the gut microbiome. 16-s rDNA and metabolomics analyses were performed to characterize differences in the gut microbiome signatures and metabolic profiles.

Key results: Plasma Ang-(1-7) was decreased in patients with sepsis. In CLP mice, exogenous Ang-(1-7) attenuated intestinal barrier dysfunction and liver damage. FMT experiments showed that the protective effects of Ang-(1-7) on the gut depended on the gut microbiota. Furthermore, 16-s ribosomal DNA analysis revealed that Ang-(1-7) treatment increased the abundance of Lactobacillus gasseri (L. gasseri) among commensal bacteria. Mechanistically, L. gasseri regulated the production of antimicrobial peptides in intestinal epithelia by activating NLRP6 inflammation.

Conclusion and implications: Ang-(1-7) protected against sepsis-induced intestine barrier dysfunction and liver injury in mice by modulating gut homeostasis and NLRP6 inflammasome. Ang-(1-7) is a promising candidate drug for protecting intestinal homeostasis in sepsis, offering new insights for clinical treatment.

Background and purpose: Interleukin (IL)-13 is implicated in airway hyperreactivity (AHR), a key feature of asthma. We explored the potential anti-AHR activity of selected specialised pro-resolving mediators (SPMs) in IL-13-induced AHR models, using human bronchial smooth muscle cells (BSMCs) and human isolated bronchi.

Experimental approach: Calcium flux responses induced by histamine or LTD₄ were assessed in BSMCs preconditioned with IL-13 and SPMs for 24 h. Human bronchi were isolated from lung tissue and preconditioned for 48 h in the presence or absence of IL-13 and SPMs. Concentration-response relationships for histamine and LTD₄ were established using myography to determine efficacy (E_max) and potency (pEC₅₀) following interventions.

Key results: In BSMCs, exposure to IL-13 increased calcium flux (E_max) triggered by histamine and LTD₄. Protectin D1 (PD1) and maresin 1 (MaR1) reversed this effect, but not lipoxin A₄, resolvin D2, and maresin-conjugate in tissue repair 3 (MCTR3). In bronchi, IL-13 exposure amplified contractions to histamine and LTD₄, and this enhancement was reversed by PD1 and MaR1. In contrast, PD1 and MaR1 added acutely during myography had no effect on agonist-induced contractility. PD1 attenuated IL-13-induced enhancement of airway contractions triggered by mast cell activation. CysLT₁ antagonism did not influence the anti-hyperreactive effect of SPMs. Chemo-informatics revealed structural similarities between PD1 and MaR1 that may explain the anti-hyperreactive action of these two SPMs.

Conclusion and implications: This new anti-hyperreactive action of PD1 and MaR1 encourages further research into their potential as therapies for the treatment of airway hyperreactivity.

Background and purpose: Anastrozole, an aromatase inhibitor, is used to treat postmenopausal women with hormone receptor-positive breast cancer, but also induces musculoskeletal pain and can lead to therapeutic regimen suspension. Aromatase inhibitors promote the release of pro-inflammatory substances from sensitised nerve fibres, which might lead to peripheral mast cell activation.

Experimental approach: We explore if tryptase released by peripheral mast cells could activate the protease-activated receptor 2 (PAR2) to sustain anastrozole-induced painful symptoms.

Key results: Anastrozole caused mechanical allodynia, muscle strength loss, and increased mast cell number and tryptase levels in the plantar tissue of male C57BL/6 mice. Depletion (using compound 48/80) or stabilisation (using ketotifen fumarate) of mast cells prevented anastrozole-induced mechanical allodynia and muscle strength loss. Compound 48/80 also prevented the increase in the number of mast cells in the plantar tissue. Tryptase inhibitors nafamostat and gabexate, or PAR2 inhibitors ENMD-1068 and AZ3451, reduced the anastrozole-induced mechanical allodynia and muscle strength loss. Furthermore, anastrozole did not cause mechanical allodynia and muscle strength loss in global (PAR2^-/-) or sensory neuron-specific (PAR2 Na_v 1.8^-/-) PAR2 knockout mice. Local sub-nociceptive doses of the PAR2 agonists (tryptase, trypsin or 2F) enhanced the anastrozole-induced mechanical sensitivity in wild-type mice, which was reduced by pre-treatment with AZ3451. PAR2^-/- or PAR2 Na_v 1.8^-/- mice treated with anastrozole did not respond to local sub-nociceptive doses of PAR2 agonists.

Conclusions and implications: Our results provide a new mechanism underlying anastrozole-induced pain, highlighting the mast cell/tryptase/PAR2 axis as a therapeutic target to manage painful symptoms.

Background and purpose: Immune tolerance prevents inflammation and autoimmunity, with dendritic cells (DCs) playing a key role. Reprogramming DCs towards a tolerogenic state represents a promising therapeutic strategy. Sulforaphane (SFN) has known immunomodulatory effects, but its clinical application is limited by poor stability and bioavailability. To enhance its therapeutic potential, SFN was conjugated with mannose (SFNMan) or fucose (SFNFuc), aiming to induce a tolerogenic phenotype in human monocyte-derived DCs (moDCs) under inflammation and to explore NFATc1's involvement.

Experimental approach: moDCs were exposed to inflammatory conditions and treated with SFN, SFNMan or SFNFuc. Their phenotype, cytokine profile, T cell-modulating capacity and NFATc1 signalling were evaluated.

Key results: SFNMan selectively induced a tolerogenic phenotype, characterised by an increased PD-L1/CD86 ratio and IL-10 production; up-regulation of SOCS1 and IDO transcripts; and Treg expansion and reduced proliferation of cytotoxic T cell proliferation. Functional assays and confocal microscopy revealed that SFNMan, but not SFNFuc, promoted NFATc1 nuclear translocation. Pharmacological inhibition of NFATc1 with cyclosporin A (CsA) abolished these effects, confirming NFATc1 as a central mediator of SFNMan-induced immune tolerance.

Conclusions and implications: Our findings identify NFATc1 as a key transcriptional switch in moDCs tolerogenic programming and highlight the carbohydrate-dependent specificity of SFN conjugates. SFNMan represents a novel carbohydrate-engineered immunomodulator capable of driving immune tolerance through NFATc1 activation. These results provide a mechanistic framework for the development of precision therapies targeting inflammatory and autoimmune diseases.

Background and purpose: Pulmonary vascular remodelling is the key pathological feature of pulmonary arterial hypertension (PAH), but treatments targeting this process are lacking. Recent studies suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors, particularly empagliflozin, may improve PAH outcomes, although the underlying mechanisms remain largely unexplored.

Experimental approach: PAH models were induced in Sprague-Dawley rats with monocrotaline or SU5416-hypoxia (SU-Hx), and empagliflozin (10 mg kg^-1 day^-1) or saline was administered orally. At the end point, haemodynamic, electrocardiographic parameters and pulmonary vascular remodelling were evaluated to investigate effects of empagliflozin in vivo. Effects of empagliflozin in vitro, were assessed using PDGF-BB-/hypoxia-induced proliferation and migration assays on human pulmonary arterial smooth muscle cells (PASMCs). Network pharmacology, molecular docking and surface plasmon resonance (SPR) were performed to explore potential mechanism(s) of empagliflozin treatment.

Key results: Empagliflozin improved haemodynamic, electrocardiographic parameters and pulmonary vascular remodelling in monocrotaline-/SU-Hx-induced PAH models. Empagliflozin inhibited PDGF-BB/hypoxia-stimulated proliferation and migration of human PASMCs and arrested cells in the G0/G1 phase in a concentration-dependent manner. Network pharmacology, biological and SPR results suggested that empagliflozin ameliorated PAH by suppressing excessive proliferation and migration of PASMCs, partly through direct binding to TYR-740, GLY-738 and ASP-737 in the tyrosine kinase effector domain of PDGFRβ, inhibiting PDGFRβ phosphorylation and downstream signalling.

Conclusions and implications: The results highlight a novel mechanism underlying the beneficial effects of empagliflozin in PAH, through direct binding to the tyrosine kinase effector domain of PDGFRβ. This interaction inhibits PDGFRβ phosphorylation, offering new insights into therapeutic strategies for PAH.

Background and purpose: Recognition and procedural memory are modulated by the noradrenergic system, whose terminals release noradrenaline along with neuropeptide Y, acting via Y1 and Y2 receptors. This study aims to investigate the role of Y1 and Y2 receptor antagonists (BMS-193885 and SF-11) on recognition and procedural memory, including their co-administration with clenbuterol, a β₂-adrenoceptor agonist, with additional focus on the molecular mechanisms underlying memory-related behavioural changes.

Experimental approach: Recognition memory was assessed in mice using the novel object recognition task. Motor learning and procedural memory were evaluated in the accelerating rotarod test. Memory-related behavioural outcomes were complemented by analyses of NPY levels, the phosphorylation status of CaMKII and ERK1/2, along with the concentrations of 5-HT, dopamine, noradrenaline and its metabolite in selected brain regions, including the prefrontal cortex, hippocampus and cerebellum.

Key results: SF-11 at 5 mg·kg^-1 impaired recognition memory, prolonged procedural memory retention and inhibited CaMKII, but at 20 mg·kg^-1, SF-11 disrupted both recognition and procedural memory increasing NPY. BMS-193885, at 5 mg·kg^-1, prolonged procedural memory retention, but at 20 mg·kg^-1, it impaired long-term recognition memory, prolonged procedural memory retention, increased NPY and decreased phospho-CaMKII. Clenbuterol enhanced procedural memory retention, but this pro-cognitive effect was diminished by co-administration with either Y receptor antagonist, which correlated with decreased noradrenaline levels.

Conclusions and implications: NPY receptor antagonists modulate memory processes in a dose- and memory-type-dependent manner, and these effects appear to be linked to hippocampal function. NPY receptors may serve as therapeutic targets to treat cognitive impairments.

RETRACTION: I. M. Adcock, Y. Nasuhara, D. A. Stevens and P. J. Barnes, “ Ligand-Induced Differentiation of Glucocorticoid Receptor (GR) Trans-Repression and Transactivation: Preferential Targeting of NF-κB and Lack of I-κB Involvement,” British Journal of Pharmacology 127, no. 4 (1999): 1003–1011, https://doi.org/10.1038/sj.bjp.0702613

The above article, published online on 29 January 2009 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley and Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party. Duplication was identified between the β2-R (media) and β2-R (RU486) western blot bands presented in Figure 3a, with the β2-R (RU486) bands being a horizontally flipped version of the β2-R (media) bands. Furthermore, analysis indicated that the third and fourth bands in the IL-1β + FP panel of Figure 4d appear to have been spliced into the panel. The authors cooperated with the investigation but could not provide original data due to the length of time that has elapsed since the study was conducted. Due to the nature of these concerns, the editors no longer have confidence in the results and conclusions of this article. The corresponding author, I. M. Adcock, disagrees with the retraction; acknowledgement of the retraction could not be obtained from the remaining co-authors.

Background and purpose: Songorine (SGR) is an alkaloid extracted from Aconitum carichaelii Debx. and has a demonstrated role in cardiac dysfunction. Chronic heart failure (CHF) is a severe clinical syndrome leading to functional impairment and death, primarily due to the deterioration of energy metabolism in cardiomyocytes. However, the precise mechanisms responsible for SGR therapeutic effects in CHF are unclear.

Experimental approach: Transverse aortic constriction (TAC) surgery was adopted to mimic heart failure in mice. Matrix-assisted laser desorption/ionisation mass spectrum image (MALDI-MSI), in combination with tissue metabolomics, revealed the distribution of different metabolites in cardiac tissue. H9c2 cells were selected as a cell model for in vitro experiments. ROS content, mitochondrial membrane potential and lysosomal activity were measured in different experimental groups.

Key results: CHF mice exhibited cardiac dysfunction, mitochondrial damage and metabolic alterations after 4 weeks. Treatment with SGR significantly improved ejection fraction, decreased autophagic levels and affected the spatial distribution of fatty acylcarnitines, a series of metabolites associated with β-oxidation. These findings suggested that SGR possessed an ameliorative effect on pressure overload-induced CHF, potentially mitigating mitochondrial damage by modulating energy metabolism. SGR administration partially reversed these alterations and restored cardiac function, enhancing the phosphorylation of mTOR and potentially mitigating the separation of mitochondria and lysosomes via the TBC1D15/Fis1/Rab7A pathway. Finally, studies on the effects of siRNA further demonstrated the critical role of SGR in mitochondrial function.

Conclusions and implications: This study provides valuable insights into the role of SGR in managing CHF via TBC1D15-mediated mitochondrial dysfunction.

Background and purpose: This study aimed to identify key effectors and their potential ligands relevant to liver cirrhosis (LC), hepatocellular carcinoma (HCC) and adjacent non-tumour tissue (ANT; reflecting the tumour-influenced yet non-cancerous liver environment rather than true disease tissue) using clinical GEO data (GSE25097) within a systems pharmacology framework.

Experimental approach: Differentially expressed genes (DEGs;|log₂FC| > 1) were identified and visualised using R software in conjunction with the STRING database. Protein-protein interaction (PPI) networks were constructed, with up-regulated and down-regulated genes depicted as blue and red circles, respectively. Candidate ligands were screened from a repository of natural organic compounds (NOCs), focussing on flavonoids and alkaloids. Kaplan-Meier Plotter (KMP), molecular docking tests (MDT) and density functional theory (DFT) analyses were employed to ensure robustness.

Key results: A total of 123 down-regulated and 146 up-regulated genes were identified and mapped into PPI networks. Among these, CCNB1, associated with the p53 signalling pathway, emerged as the most significantly up-regulated gene across LC, HCC, and ANT tissues. Flavopiridol, a flavonoid-based inhibitor, was initially highlighted; however, subsequent screening identified coronaridine hydroxyindolenine (CH), an alkaloid, as the most promising candidate. CH demonstrated superior binding affinity compared to flavopiridol in both MDT and DFT analyses.

Conclusion and implications: The CH-CCNB1 complex exhibited high stability, indicating that CH may represent potential candidate warranting further study against LC, HCC and ANT.