British Journal of Pharmacology最新文献

Background and purpose: Despite breakthroughs in immunotherapy and targeted therapies, chemotherapy remains indispensable in oncology.

Experimental approach: This study seeks to pinpoint key pathways in doxorubicin (DOX)-treated mouse hippocampus, utilising comprehensive transcriptomic and metabolomic analyses, and validating the mechanisms in vitro and in vivo.

Key results: Our multi-omics investigation revealed that sustained DOX exposure induced significant down-regulation of 5-aminolevulinate synthase 2 (ALAS2) and its catalytic product 5-aminolevulinic acid (5-ALA) in the hippocampal region. ALAS2 deficiency was specific to hippocampal neurons, which were more sensitive to oxidative damage than astrocytes or microglia. In vivo and in vitro studies demonstrated that 5-ALA administration or ALAS2 overexpression protected the brain from DOX-induced neurotoxicity. ALAS2 catalyses the condensation of glycine and succinyl-CoA to form 5-ALA, the key precursor of haem. Beyond its role in erythropoiesis, haem is a metabolite that modulates cellular redox homeostasis through interactions with the BACH1 (BTB and CNC homology 1)/NRF2 (nuclear factor erythroid 2 like 2) pathway. We found that DOX suppressed the ALAS2/5-ALA axis, thereby enhancing BACH1 stability. This stabilised BACH1 competes with NRF2 for binding to antioxidant response elements (AREs) in target gene promoters. Conversely, reinforcing the ALAS2/5-ALA axis elevated intracellular haem levels, promoting BACH1 degradation and enhancing NRF2 activity. Using a zebrafish model, we further highlighted the antioxidant and neuroprotective role of 5-ALA against DOX-induced neurotoxicity.

Conclusions and implications: In conclusion, this study elucidates a novel endogenous neuroprotective mechanism wherein the ALAS2/5-ALA axis modulates the BACH1/NRF2 pathway. 5-ALA shows promise for repurposing to mitigate chemotherapy-associated neurotoxicity.

Background and purpose: EZH2 (enhancer of zeste homologue 2) inhibitors are an emerging class of drugs that target epigenetic regulation. However, their efficacy in solid tumours has been limited, partly due to drug-induced upregulation of fatty acid synthesis. Combining lipid metabolic modulation with EZH2 inhibition may offer a promising strategy to enhance antitumor activity.

Experimental approach: We conducted a screen of clinically approved lipid-lowering drugs to identify candidates that could enhance the efficacy of EZH2 inhibitors and found that fenofibrate significantly potentiated the antitumor effects of EZH2 inhibition. Mechanistic studies revealed that this synergistic effect was associated with the degradation of EZH2 protein. To uncover the underlying regulatory pathway, we performed mass spectrometry analysis, which identified the E3 ubiquitin ligase TRIM21 and the deubiquitinase OTUD4 as key mediators of fenofibrate-induced EZH2 degradation.

Key results: Fenofibrate significantly enhanced the antitumor effects of EZH2 inhibitors in melanoma, independent of its conventional lipid-lowering function. TRIM21 and OTUD4 were identified as critical mediators of this synergistic effect. Fenofibrate disrupted the non-canonical functions of EZH2 by promoting its destabilization, thereby exerting dual effects-inhibiting EZH2 enzymatic activity and accelerating its degradation. Combination therapy with fenofibrate and EZH2 inhibitors resulted in a potent synergistic suppression of tumour growth.

Conclusions and implications: Our findings reveal a previously unrecognized role for fenofibrate in augmenting EZH2-targeted therapy. This study provides a novel strategy to improve the efficacy of epigenetic therapies in cancer by combining EZH2 inhibitors with fenofibrate, offering potential clinical benefits for precision oncology.

Background and purpose: Spleen tyrosine kinase (SYK) has broad biological functions in inflammation and immunity. The orally administered SYK inhibitor BI 894416 was investigated in a single-rising-dose Phase I study in healthy volunteers and in a combined single- and multiple-rising-dose Phase Ib study in patients with mild asthma.

Experimental approach: The single-blinded, partially randomised, placebo-controlled Phase I study evaluated single doses of BI 894416 (3-70 mg) in healthy volunteers. The single-blinded, randomised, placebo-controlled Phase Ib study in patients with mild asthma evaluated three single doses (75-170 mg) and four multiple doses (10-60 mg) of BI 894416 over an interval of 9 days. The primary objective of both studies was safety and tolerability, assessing the proportion of participants with drug-related adverse events (AEs). Secondary endpoints related to pharmacokinetics and efficacy (Phase Ib study only).

Key results: All except one randomised participant completed treatment (56 healthy volunteers and 68 mild asthmatics [29 received a single dose and 39 received multiple doses]). The most frequent drug-related AEs were headache, diarrhoea and nausea (all of mild/moderate intensity). No serious AEs occurred. BI 894416 was rapidly absorbed with median time-to-peak concentration 0.5-1.0 h; exposure increased in a dose-dependent manner. Basophils and nasal epithelial cells showed dose-dependent modulation of activation- and disease-associated genes and pathways.

Conclusion and implications: BI 894416 was safe and well tolerated in healthy volunteers and mild asthmatics. Results from target engagement biomarkers demonstrated treatment- and dose-dependent cellular modulation, potentially leading to decreased airway inflammation and airway obstruction.

Depression, a complex global disorder with unmet therapeutic needs, imposes profound societal burdens. Yueju Pill (YJP), a classic TCM formula targeting 'six stagnations', synergistically integrates five herbs (Atractylodes, Cyperus, Ligusticum, Gardenia and Massa Medicata) to restore Qi-blood homeostasis. Contemporary evidence delineates its multitarget antidepressant efficacy: normalising monoaminergic neurotransmission and the tryptophan-kynurenine pathway, potentiating neurotrophic support (BDNF/eEF2) for neuroplasticity, antagonising neuroinflammation via microglial M1-to-M2 polarisation and NF-κB/MAPK inhibition, mitigating oxidative stress and mitochondrial dysfunction and enhancing synaptic plasticity through glial/neuronal gene regulation (e.g., GADD45g/PHGDH). This synthesis of TCM principles with mechanistic evidence positions YJP as a holistic, systems-level therapeutic candidate, advocating for rigorous clinical validation and integration into precision psychiatry.

Background and purpose: Regular physical activity is an effective non-pharmacological approach to hypertension management and maternal exercise improves offspring cardiovascular health, although mechanisms remain unclear. A-kinase anchoring protein 150 (AKAP150) targets protein kinase Cα to L-type Ca²⁺ channels (Ca_V1.2), enhancing vascular tone in arterial smooth muscle during hypertension. This study aims to uncover a novel mechanism in which epigenetic modifications of the AKAP150 gene (Akap5) mediate the beneficial effects of maternal exercise on vascular function in hypertensive offspring.

Experimental approach: Pregnant spontaneously hypertensive rats (SHRs) and smooth muscle-specific AKAP150 knock-in mice (AKAP150 smKI) were assigned to sedentary or exercise groups. Mesenteric arteries (MAs) from embryonic day 21 and 3-month-old offspring were analysed for vascular function, electrophysiology, gene expression and Akap5 promoter histone acetylation.

Key results: Maternal exercise during pregnancy significantly reduced blood pressure and Ca_v1.2 channel function in adult male offspring of both SHR and AKAP150 smKI, but not in female SHR offspring. Maternal exercise significantly attenuated AKAP150-Ca_v1.2 association in mesenteric arterial myocyte from SHR offspring. Additionally, it decreased H3K9ac at the Akap5 gene promoter, with a concomitant decrease in AKAP150 protein and mRNA expressions in hypertensive offspring. Furthermore, maternal exercise activated AMPK that up-regulated silent information regulator 1 (sirtuin 1; SIRT1) in the mesenteric arteries of SHR offspring.

Conclusions and implications: Maternal exercise improves blood pressure and vascular function in adult male hypertensive offspring by deacetylating H3K9ac at the Akap5 promoter via AMPK/SIRT1 activation. This highlights prenatal exercise as a potential strategy to mitigate the intergenerational transmission of hypertension.

Background and purpose: Adenosine is a potent regulator of neurotransmission and neuronal excitability, through activation of G_i coupled adenosine A₁ receptors (A₁Rs). Adenosine has gained interest as an anticonvulsant because of its endogenous involvement in ending seizure activity, but peripheral side effects require local application. We recently developed a coumarin-caged derivative of the A₁R agonist N⁶-cyclopentyl-adenosine (CPA), which can be used to release CPA with millisecond light flashes. In the hippocampal neuronal network, CPA reduces excitability.

Experimental approach: A closed-loop feedback system recorded field potentials evoked in male rat hippocampal slices on a 64-channel multielectrode array; it extracted relevant parameters and used an algorithm to photorelease CPA to control and limit excitability. Raising extracellular K⁺ concentration to 8.5 mM, a common ex vivo epilepsy model induced regularly occurring epileptiform bursts, when it was still possible to monitor field potentials.

Key results: The reduction of excitability in response to CPA photorelease was quantified, and the feedback system was analysed and fine-tuned. Eventually, the feedback system was able to automatically evolve to a setpoint that almost completely suppressed the epileptiform bursts, whilst maintaining about ~50% of baseline neurotransmission. This not only offers a new strategy to fight difficult to treat epilepsies but also creates a research platform for the study of neuronal networks in a well-defined state of excitability.

Conclusions and implications: Combining photopharmacological adenosinergic modulation with real-time field potential monitoring provides a first step towards closed-loop precision treatment for diseases related to neuronal hyperexcitability, such as epilepsy.

Background and purpose: Pentagalloylglucose (PGG), a natural hydrolysable gall tannin, has limited bioavailability, and its biological activities are concentrated in the digestive system. However, our study discovered that this nonabsorbable compound can improve allergic asthma. This study focuses on elucidating the mechanisms underlying PGG's anti-allergic asthma effects.

Methods: PGG serum metabolites were analyzed by UPLC/Q-TOF MS. To further explore its mechanisms, 16S rRNA sequencing, qPCR, and UPLC/Q-TOF MS were used to assess gut microbiota and metabolites. Fecal microbiota transplantation from PGG-treated mice into antibiotic-treated asthmatic mice evaluated its microbiota-dependent effects. Flow cytometry analyzed PGG's modulation of pulmonary ILC2s in a murine asthma‑colitis comorbid model.

Key results: PGG's serum metabolites were below the quantification limit. PGG administration improved colonic injury and modulated L. reuteri; notably, exogenous L. reuteri alleviated asthma via increasing I3A from Trp metabolism. However, fecal microbiota transplantation from PGG-treated mice did not alleviate asthma, and PGG remained effective in microbiota-depleted mice, suggesting its action is microbiota-independent. Furthermore, PGG alleviated intestinal inflammation in both normal and antibiotic-treated asthmatic mice. In a comorbid colitis-asthma model, PGG counteracted colitis-aggravated asthma symptoms by modulating lung ILC2s.

Conclusion and implications: Although PGG modulates the gut microbiota and related metabolites, its anti-asthmatic effect is not primarily dependent on this pathway. Notably, it can ameliorate lung ILC2 dysregulation by alleviating enteritis.

Background and purpose: The rising prevalence of type 2 diabetes mellitus (T2D) has led to an increase in complications, including mild cognitive impairment. Accordingly, there is a growing interest in the potential neuroprotective benefits of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT2is). Although clinical studies suggest that these drugs mitigate cognitive decline, the underlying mechanisms remain unclear. This study aimed to elucidate the potential mechanisms through which DPP-4is or SGLT2is, in combination with metformin, confer neuroprotection.

Experimental approach: We conducted a cross-sectional study involving T2D patients on either metformin alone or in combination with a DPP-4i or SGLT2i, alongside healthy controls. Cognitive and metabolic phenotypes were assessed, followed by serum proteomic profiling, computational drug target prediction, network analyses and molecular docking to identify signalling pathways linked to cognitive impairment.

Key results: T2D patients on combination therapy demonstrated better cognitive function, independent of other phenotypic, metabolic and biochemical factors. Proteomic profiling revealed 36 differentially expressed proteins that were preserved or restored to control levels in the combination therapy group. Gene set enrichment analysis highlighted the modulation of the complement pathway, particularly the involvement of ficolin-3 (FCN3). Molecular docking suggested that the sugar-like or glycyl moieties in anti-diabetic drug molecules interacted with FCN3, potentially inhibiting complement system activation. Such interaction was confirmed by binding studies using surface plasmon resonance.

Conclusion and implications: These findings are significant in tailoring T2D treatment to reduce cognitive complications and exploring drug design to target neuroinflammatory disorders.

Background and purpose: Dopamine receptor agonists, particularly targeting the dopamine D_2L receptor (D_2LR), have been used to treat Parkinson's disease (PD). However, valvular heart disease and somnolence, mainly caused by activating the serotonin 5-HT_2B receptor (5-HT_2BR) and dopamine D₃ receptor (D₃R), respectively, currently challenge their clinical use. Here, we aimed to develop a novel dopamine receptor agonist with superior therapeutic efficacy for PD, while minimising adverse reactions.

Experimental approach: Matsupexole, a novel nonergot dopamine receptor agonist, was evaluated by agonist activity for D_2LR and a 6-hydroxydopamine-lesioned male rat PD model. To explore its adverse effects, the agonist activity for other receptors, including 5-HT_2BR and D₃R, and the resulting porcine heart valve interstitial cell (PHVIC) proliferation and non-rapid eye movement (REM) sleep induction in male rats were evaluated, in comparison with existing dopamine receptor agonists.

Key results: Matsupexole exhibited potent agonist activity for D_2LRs without inducing 5-HT_2BR activation or promoting PHVIC proliferation. Matsupexole demonstrated sustained efficacy in the PD model. In contrast, despite its strong D_2LR agonist activity, cabergoline, an ergot dopamine receptor agonist, significantly evoked PHVIC proliferation. Reflecting its higher D_2LR/D₃R selectivity, matsupexole did not affect non-REM sleep induction. Although pramipexole, a D₃R-favouring nonergot agonist, showed efficacy in the rat PD model, its effect was shorter in duration, and it strongly promoted non-REM sleep. The stabilised interaction between Val190^5.39 in D_2LR and matsupexole, but not pramipexole, further supports the higher D_2LR/D₃R selectivity of matsupexole.

Conclusion and implications: Matsupexole is a promising future, potentially best-in-class dopamine receptor agonist for treating PD.

Gastric inhibitory polypeptide (GIP)/Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly prescribed for the management of obesity and type 2 diabetes, yet research pertinent to their effects on muscle health is limited. Considering the central role of muscle strength as a sarcopenia component, this article summarizes emerging evidence on insulin-based therapies and muscle strength. Short-to-mid-term trials of semaglutide or liraglutide in adults with obesity have shown statistically preserved handgrip strength despite reductions in lean soft tissue mass, suggesting that muscle strength may not decline proportionally to weight loss. Likewise, tirzepatide combined with resistance and aerobic training in young men may not confer additional strength benefits beyond exercise alone. In contrast, longitudinal and retrospective research in older adults with type 2 diabetes have reported reductions in handgrip strength and accelerated sarcopenia with prolonged semaglutide use, raising concerns about potentially detrimental effects on neuromuscular health. Collectively, these findings indicate that lean soft tissue loss is not a reliable predictor of muscle strength change following GIP/GLP-1 agonists. While shorter term studies suggest relative preservation, longer term data in older adults point to possible risk of muscle strength decline. Future randomized, double-blinded trials with adequate sample sizes and longer follow-ups are warranted, particularly in older populations who are at an increased risk of sarcopenia. Their findings could support the integration of muscle strength outcomes into clinical monitoring and trial design to ensure that GIP/GLP-1 agonist-based strategies may not compromise muscle strength in these populations during weight loss.