British Journal of Pharmacology最新文献

Background and purpose: Silicosis is a major cause of occupational disease-related morbidity and mortality worldwide, yet effective pharmacological treatments remain limited. Nerandomilast, a novel inhibitor of phosphodiesterase-4B (PDE4B), has demonstrated anti-fibrotic potential in idiopathic pulmonary fibrosis (IPF); however, its efficacy and mechanisms in silicosis have not been investigated.

Experimental approach: The therapeutic effects (and their underlying mechanisms) of PDE4B inhibition was evaluated in in models of silicosis, both in vivo (male C57BL/6N mice) and in vitro (THP-1 macrophages and MRC-5 cells). Single-cell RNA sequencing, using lung tissue, was first performed to identify PDE4B as a key regulatory target in the pathogenesis of silicosis. Based on this finding, the therapeutic effects and underlying mechanisms of PDE4B inhibition were assessed using nerandomilast. Pulmonary function tests, inflammatory marker analyses and fibrosis evaluations were conducted to determine treatment efficacy. In addition, bulk RNA sequencing and transcriptomic analyses were performed to explore the molecular pathways modulated by nerandomilast.

Key results: PDE4B inhibition effectively prevented and attenuated silica-induced lung inflammation in the mouse model by suppressing both canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Furthermore, PDE4B inhibition down-regulated TGF-β/Smad signalling in lung fibroblasts of silicosis, leading to a significant reduction in fibrosis-related gene expression.

Conclusions and implications: These findings suggest that nerandomilast, a PDE4B inhibitor, may be a promising treatment for silicosis, which currently lacks effective therapies.

Fibrosis, a consequence of dysregulated wound healing underlying chronic diseases such as metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel disease (IBD), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (PF) and systemic sclerosis (SSc), accounts for nearly 45% of deaths in developed countries. Fibrosis is driven by persistent epithelial injury and aberrant communication among epithelial, mesenchymal, and immune cells, leading to fibroblast activation, myofibroblast accumulation, and excessive extracellular matrix (ECM) deposition. Despite its clinical significance, antifibrotic therapy remains largely limited to pirfenidone and nintedanib for PF and resmetirom for MASH. The continued failure of many candidates in clinical development highlights the persistent unmet need for more effective antifibrotic approaches. FFA1 (GPR40) and FFA4 (GPR120) are free-fatty acid receptors (FFAR) that sense medium- and long-chain fatty acids, primarily coupling to Gα_q/11 and β-arrestin signalling pathways to regulate diverse physiological processes. Although these FFAR have been extensively investigated in the context of metabolic disorders, emerging evidence indicates that FFA1 and FFA4 also play critical roles in the pathophysiology of fibrosis across multiple organs. This review highlights the roles of FFA1 and FFA4 in mitigating fibrosis, either directly or indirectly, across various organs, including the liver, kidney, lung, heart, and peritoneum, as well as in disorders associated with fibrosis-related injuries.

Schizophrenia is regarded as a complex and heterogeneous psychiatric disorder, characterised by diverse symptoms and comorbidities, which complicate both clinical management and drug development. Current pharmacological treatment, primarily based on dopamine D₂ receptor antagonism or partial agonism, which has not markedly progressed since the emergence of chlorpromazine in the 1950s, remains inadequate in addressing the full spectrum of clinical symptoms. Despite decades of preclinical research, many novel compounds with different mechanisms that show efficacy in animal models subsequently fail in Phase II or III clinical trials. This translational gap may reflect limitations in model selection, reliance on behavioural endpoints with poor clinical correspondence and the inherent inability of rodent paradigms to capture the full heterogeneity of human schizophrenia. This review provides a systematic overview of how rodent models and behavioural assays have been applied by the pharmaceutical industry over the past 30 years to evaluate antipsychotic efficacy, both for marketed drugs and investigational compounds entering first-in-human (FIH) clinical trials. We examine the extent to which these models have informed regulatory submissions and clinical development, whilst also analysing the translational challenges that arise from their limited ability to capture the complexity and heterogeneity of schizophrenia, as well as the impact of inclusion criteria on the testing of antipsychotic drug efficacy. By highlighting these limitations, we propose key considerations for refining model selection, behavioural endpoints, and biomarker integration to strengthen the predictive value of preclinical research and improve the likelihood of success for novel antipsychotics in clinical trials.

Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold increase in neuropsychiatric co-morbidities among individuals with chronic pain, where epigenetic dysregulation serves as a key mechanism linking ongoing pain to emotional disorders. This review systematically explores epigenetic signatures in supraspinal integration hubs, notably the limbic-paralimbic networks and prefrontal regulatory circuits. The identified epigenetic signatures encompass dysregulation of DNA methyltransferases (DNMTs), RNA modifications, histone post-translational modifications and locus-specific alterations, including aberrant methylation at the brain-derived neurotrophic factor (BDNF), opioid μ receptor and transient receptor potential ankyrin 1 (TRPA1) gene loci. Additionally, they involve dysfunction of the glucocorticoid receptor (GR)/corticotropin-releasing factor (CRF) axis via epigenetic modulation. Building on these findings, we evaluate therapeutic strategies addressing epigenetic dysregulation. While preclinical data demonstrate the efficacy of histone deacetylase (HDAC) and DNMT inhibitors, clinical translation faces significant barriers, including limited blood-brain barrier permeability. Notably, our analysis highlights the benefits of combining pharmacological interventions with non-invasive neuromodulation for enhanced co-morbidity management. Looking forward, this review proposes innovative approaches that leverage CRISPR-based chromatin editing platforms, biomimetic nanocarriers for neuron-specific delivery and closed-loop neuromodulation integrating real-time biomarker feedback, collectively establishing a precision medicine framework for pain or neuropsychiatric co-morbidities.

Background and purpose: Ventricular arrhythmias are a leading cause of death among patients with cardiovascular diseases and are associated with elevated levels of catecholamines. Mitochondrial Ca²⁺ transport is essential for initiating an adrenergic response. However, continuous stimulation might lead to mitochondrial Ca²⁺ overload and dysfunction within cardiac tissue. This study investigates the role of mitochondrial Ca²⁺ in lethal arrhythmogenesis and the effects of its modulation.

Experimental approach: Male C57BL/6 mice were administered either Ru360 (oxo-bridged dinuclear ruthenium ammine complex) a potent and selective mitochondrial Ca²⁺ transport inhibitor, or normal saline via intravenous injection. A baseline electrocardiogram (ECG) was recorded, followed by subcutaneous administration of isoprenaline. The ECG was monitored for an additional 20 min, after which cardiomyocytes and mitochondria were isolated for further characterization studies.

Key results: Isoprenaline administration led to ventricular tachycardia and fibrillation, but Ru360 pretreatment successfully prevented these arrhythmias. Mitochondria from isoprenaline-treated hearts showed higher Ca²⁺ content, indicating overload that compromised mitochondrial function and membrane integrity, evidenced by decreased respiratory control, reduced Ca²⁺ retention capacity and diminished membrane potential. Isoprenaline also increased oxidative stress, illustrated by elevated peroxide production, electron leak and acute oxidative modifications, and erratic cellular Ca²⁺ dynamics. This mitochondrial dysfunction correlated with a decreased respirasome activity, but not a difference in respirasome abundance quantified by complexome profiling, which was prevented by Ru360 pretreatment.

Conclusion: Mitochondrial Ca²⁺ overload significantly contributes to arrhythmias by disrupting respirasome function and increasing oxidative stress, impairing cellular Ca²⁺ dynamics. Modulating mitochondrial Ca²⁺ transport might be a promising strategy for developing innovative antiarrhythmic therapies.

The growth in detailed multi-omic profiling has created new opportunities to tailor clinical care and therapy to patient-level variations in disease phenotype. However, efforts towards precision medicine and personalised therapeutics are hampered by limitations in identifying biologically relevant signals that correlate with and underlie disease activity and therapeutic response from these growing arrays of data. These complexities are accentuated further when attempting to translate the new insights in disease pathobiology into new drug targets for treatment. Additionally, understanding how best to reposition existing drugs in the context of new data on disease pathogenesis remains a challenge. Network medicine provides one approach to comprehend these large data sets and identify better the key molecular and phenotypic signals that can function as disease and treatment biomarkers and that can be targeted for therapy. In this review, we discuss basic concepts in the application of network science to biological systems and then build on these concepts to discuss network-based approaches for identifying novel disease biomarkers, elucidating new drug targets and repositioning existing drugs for new indications. LINKED ARTICLES: This article is part of a themed issue Network Medicine and Systems Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.8/issuetoc.

Background and purpose: Inositol hexaphosphate (IP6) is a natural carbohydrate compound in plants and mammalian cells. We aimed to investigate whether IP6 could protect cochlear hair cells and ameliorate sensorineural hearing loss (SNHL) in multiple experimental mouse models of SNHL.

Experimental approach: Three SNHL female mouse models were designed, namely (1) a model induced by the chemotherapy drug cisplatin (3 mg kg^-1, intraperitoneal [i.p.] injection), (2) a model induced by aminoglycosides (kanamycin, 1 g kg^-1, subcutaneous injection; furosemide 0.1 g kg^-1, i.p. injection), and (3) an age-related hearing loss (ARHL) mouse model. For IP6 treatments, IP6 (40 or 80 mg kg^-1) was injected i.p. into multiple mouse models to investigate its protective effects on SNHL and ARHL. In addition, another group of mice was fed 2% IP6 (added in their drinking water) to investigate its protective effects on ARHL.

Key results: The collected ABR data suggested that IP6 (80 mg kg^-1) significantly reduced hearing threshold shifts in all three female mouse models. Furthermore, the collected immunohistochemical staining data suggested that IP6 significantly ameliorated the loss of outer hair cells in all three mouse models.

Conclusion and implications: These findings support further investigation of IP6 as a potential otoprotective agent for future clinical translation.

Background and purpose: Targeting the retinoid-related orphan receptor α (RORα) signalling pathway represents a promising therapeutic strategy for cardiovascular diseases comorbid with insomnia. Here, we identify 6‴-feruloylspinosin (6-FS) as a potent RORα activator and investigate its therapeutic efficacy and underlying mechanisms in HF accompanied by insomnia.

Experimental approach: Transverse aortic constriction (TAC) was conducted to induce heart failure comorbid with insomnia. Echocardiography, histopathology and serum biochemical indicators were examined. Transcriptomics analysis, molecular docking, surface plasmon resonance binding assays, cellular thermal shift and microscale thermophoresis assays were performed. Subsequently, the mechanisms underlying 6-FS-mediated protection were elucidated through Western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC).

Key results: 6‴-Feruloylspinosin (6-FS) effectively improved cardiac function and mitigated myocardial injury in the mice model of TAC-induced HF. 6-FS attenuated pressure overload-induced cardiac hypertrophy and significantly improved insomnia and anxiety-like behaviours through modulation of neurotransmitter systems. 6-FS ameliorated insomnia through restoration of tight junction integrity and suppression of neuroinflammation. Mass spectrometry analysis confirmed the presence of 6-FS in both cardiac and cerebral tissues, and transcriptomic analysis demonstrated a marked up-regulation of RORα following 6-FS administration. Mechanistically, 6-FS exhibited the strongest binding affinity for RORα and simultaneously enhanced RORα-mediated regulation of the JAK2/STAT3 signalling pathway. Importantly, RORα inhibition completely abrogated the protective effects of 6-FS against TAC-induced cardiac hypertrophy and insomnia.

Conclusions and implications: Our findings highlight 6-FS as a novel RORα activator with dual cardioprotective and sleep-enhancing benefits, offering new insights into the prevention and treatment of cardiovascular diseases with comorbid sleep disturbances.

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.

Linked articles: This article is part of a themed issue Network Medicine and Systems Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.8/issuetoc.

Background and purpose: Neutrophil extracellular traps (NETs) play a key role in the local and systemic pathologies induced by Echis carinatus and Naja naja venoms. This study aimed to identify the toxin/s responsible for N. naja venom-induced NET formation.

Experimental approach: N. naja venom was subjected to molecular sieving to identify the toxins responsible for NET formation. The venom was fractionated, and the third fraction, cytotoxin fraction (CTXF), was found to induce vital NET formation. Various in vivo and in vitro experiments were conducted to comprehend the effects and mechanisms involved, including histochemical and immunohistochemical studies. To draw appropriate conclusions, CTXF was comparatively characterised along with purified cardiotoxin (Np-CTX), neurotoxin (Nn-NTX), and phospholipase A₂ (VRV-PL-XII).

Key results: CTXF is a non-enzymatic cytotoxin fraction. Peptide analysis revealed that CTXF is a mixture of four cytotoxins/cardiotoxins of molecular mass ranging from 6668 to 6778 Da, and they belong to the 3FTx family. In vivo studies demonstrated that CTXF damaged cardiac muscle extensively, where CTXF and H3Cit specifically localised in the cardiac tissue. CTXF and Np-CTX induced the formation of NETs, whereas Nn-NTX and VRV-PL-XII did not. NET formation was associated with increased intracellular Ca²⁺ flux via the store-operated Ca²⁺ entry mechanism, accompanied by alterations in actin dynamics.

Conclusions and implications: This study identified N. naja venom cytotoxins/cardiotoxins of the 3FTx family as key inducers of NETs. The NET-forming mechanism involves a cytosolic Ca²⁺ spike, resulting in cytoskeletal rearrangements, highlighting potential therapeutic targets for mitigating venom-induced pathologies.