British Journal of Pharmacology最新文献

Background and purpose: Gene regulation is frequently altered in diseases in unique and patient-specific ways. Hence, personalised strategies have been proposed to infer patient-specific gene-regulatory networks. However, existing methods do not scale well because they often require recomputing the entire network per sample. Moreover, they do not account for clinically important confounding factors such as age, sex or treatment history. Finally, a user-friendly implementation for the analysis and interpretation of such networks is missing.

Experimental approach: We present DysRegNet, a method for inferring patient-specific regulatory alterations (dysregulations) from bulk gene expression profiles. We compared DysRegNet to the well-known SSN method, considering patient clustering, promoter methylation, mutations and cancer-stage data.

Key results: We demonstrate that both SSN and DysRegNet produce interpretable and biologically meaningful networks across various cancer types. In contrast to SSN, DysRegNet can scale to arbitrary sample numbers and highlights the importance of confounders in network inference, revealing an age-specific bias in gene regulation in breast cancer. DysRegNet is available as a Python package (https://github.com/biomedbigdata/DysRegNet_package), and analysis results for 11 TCGA cancer types are available through an interactive web interface (https://exbio.wzw.tum.de/dysregnet).

Conclusion and implications: DysRegNet introduces a novel bioinformatics tool enabling confounder-aware and patient-specific network analysis to unravel regulatory alteration in complex diseases.

J. Cross, G. R. Stenton, C. Harwig, C. Szabo, T. Genovese, R. Di Paola, E. Esposito, S. Cuzzocrea, and L. F. Mackenzie, “ AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis,” British Journal of Pharmacology 174, no. 18 (2017): 3045–3057, https://doi.org/10.1111/bph.13934

In the published version of the article, duplication has been detected between the “30 mg•kg⁻¹” panel in Figure 1A and the “Sham” panel in Figure 1B. In the corrected Figure 1A, below, the “30 mg•kg⁻¹” panel has been replaced with the correct one.

The authors confirm that all the experimental results and corresponding conclusions mentioned in the paper remain unaffected.

The authors apologize for the mistake and for the inconvenience caused.

Background and purpose: Our previous study reported that fructose intake increased systemic blood pressure and reduced nitric oxide (NO) in the nucleus tractus solitarius (NTS) due to oxidative stress and neuroinflammation. However, it remains unclear how reactive oxygen species (ROS) reduce NO and how this process impacts neuroinflammation in the NTS. This study aimed at investigating the effect of ROS on acetylation of high mobility group box 1 protein (HMGB1) in the NTS of fructose-induced hypertensive rats.

Experimental approach: Male Wistar-Kyoto (WKY) rats were fed with 10% fructose water to elevate blood pressure. Thereafter, CLI-095 and glycyrrhizic acid (GA) treatments were delivered for up to 2 weeks (1 mg·12 μL^-1·day^-1, by intracerebroventricular injection) to reduce the negative effects of toll-like receptor 4 (TLR4) and HMGB1 activation.

Key results: Two weeks of CLI-095 and GA treatment reduced systemic blood pressure and significantly preserved neuronal and endothelial nitric oxide synthase (nNOS and eNOS) availability against the inflammatory insults of fructose consumption. Both CLI-095 and GA halted the interaction of acetylated HMGB1 and TLR4. Two weeks of CLI-095 and GA treatment markedly reduced NTS inflammation (pro-inflammatory cytokines and microglial activation) and lowered serum norepinephrine levels.

Conclusion and implications: Our data reveal novel pharmacological properties for CLI-095 and GA, which improved blood pressure and inflammatory conditions by decreasing the interaction of acetylated HMGB1 with TLR4. These findings challenge the commonly accepted dogma that essential hypertension is specifically mediated by neuroinflammation due to acetylated HMGB1 coupling to TLR4.

Hypertension is a major contributor to cardiovascular disease and its associated morbidity and mortality. The low efficacy observed with some anti-hypertensive therapies has been attributed partly to inter-individual genetic variability. This paper reviews the major findings regarding these genetic variabilities that modulate responses to anti-hypertensive therapies such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, calcium channel blockers (CCBs) and β-adrenoceptor blockers. The importance of studying these genetic polymorphisms stems from the goal to optimise anti-hypertensive therapy for each individual patient, aiming for the highest efficacy and lowest risk of adverse effects. It is important to recognise that environmental and epigenetic factors can contribute to the observed variations in drug responses. Owing to the multigenic and multifactorial nature of drug responses, further research is crucial for translating these findings into clinical practice and the establishment of reliable recommendations.

EXPRESSION OF CONCERN: S. Cuzzocrea, B. Pisano, L. Dugo, A. Ianaro, N. S. A. Patel, R. Di Paola, T. Genovese, P. K. Chatterjee, M. Di Rosa, A. P. Caputi, and C. Thiemermann, “ Rosiglitazone and 15-deoxy-Δ^12,14-prostaglandin J₂, ligands of the peroxisome proliferator-activated receptor-γ (PPAR-γ), reduce ischaemia/reperfusion injury of the gut,” British Journal of Pharmacology 140, no. 2 (2003): 366–376, https://doi.org/10.1038/sj.bjp.0705419.

This expression of concern is for the above article, published online on 2 February 2009 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley & Sons Ltd. The expression of concern has been agreed due to third-party concerns related to the data presented in the article. Indicators for cloned image elements and inappropriate undeclared image modification were found in multiple image parts and several panels in Figures 1, 9, and 11. Due to the significant time elapsed since publication, the authors were unable to provide the original images. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers.