British Journal of Pharmacology最新文献

Background and purpose: Doxorubicin has been used widely for the treatment of human cancer but its clinical use is limited by cardiotoxicity. We examined the effect of the pan-NADPH oxidase inhibitor Vas2780 on myocyte ferroptosis and cardiac remodelling and function in a clinically relevant mouse model of chronic doxorubicin-induced cardiomyopathy and the underlying mechanisms.

Experimental approach: Sixty-five mice were randomized to receive saline, Vas2870 (2 mg·kg^-1, i.p., once a day for 40 days), doxorubicin (3 mg·kg^-1, i.p., every other day, six times) or doxorubicin plus Vas2870 (n = 10-22).

Key results: Doxorubicin-treated mice exhibited a decrease in left ventricular (LV) fractional shortening and an increase in the ratio of lung wet-to-dry weight, indicating LV systolic dysfunction and lung congestion, and these alterations were prevented by the Vas2870 treatment. In doxorubicin-treated mice, myocardial levels of gp91phox, malondialdehyde and 4-hydroxynonenal were increased; SLC7A11, GPX4, FTH1 and FPN proteins were decreased; TfR1 (CD71) protein and myocardial iron levels were elevated and ALAS1 was reduced. Vas2870 inhibited myocardial lipid peroxidation, prevented decreased SLC7A11 and GPX4 proteins, normalized dysregulated iron metabolism-related proteins, increased ALAS1 protein and upregulated mitochondrial genes, resulting in the prevention of iron overload and ferroptosis in doxorubicin-induced cardiomyopathy. Similarly, Vas2870 prevented doxorubicin-induced ferroptosis in H9C2 cardiomyocytes.

Conclusion and implications: Vas2870 prevents myocyte ferroptosis through inhibition of lipid peroxidation, GPX4/SLC7A11 downregulation and disruptions in iron metabolism, leading to the amelioration of doxorubicin-induced heart failure. Therapies directed at inhibiting NADPH oxidase and/or ferroptosis may be of value in the treatment of heart failure.

Background and purpose: The development of drug tolerance following prolonged use of opioids, such as morphine, limits their analgesic efficacy and clinical utility. Epigenetic modifications, particularly N⁶-methyladenosine (m⁶A), have garnered increasing research interest. AlkB homologue 5 (ALKBH5), a key m⁶A demethylase, has been implicated in cancers and neurological disorders. However, its role in morphine tolerance remains unclear.

Experimental approach: A mouse model of morphine tolerance was established via repeated subcutaneous morphine administration. The m⁶A methylation levels and related enzymes expression in the spinal cord were assessed. Functional validation was conducted via adeno-associated virus (AAV)-mediated ALKBH5 overexpression in the spinal dorsal horn. Next-generation sequencing and GO/KEGG pathway analysis were performed to identify potential downstream target genes, followed by validation via pharmacological inhibition of SGK1.

Key results: Morphine-tolerant mice exhibited significantly elevated spinal m⁶A methylation, mainly because of reduced ALKBH5 expression in superficial dorsal horn neurons. ALKBH5 overexpression attenuated the development of morphine tolerance and partly restored opioid analgesic efficacy, reducing spinal m⁶A methylation levels and SGK1 expression. Transcriptomic analysis and subsequent validation identified SGK1-associated immune signalling pathways as a pivotal mediator of morphine tolerance.

Conclusions and implications: Decreased expression of ALKBH5 contributes to elevated spinal m⁶A methylation and SGK1 expression, promoting morphine tolerance. Targeted overexpression of ALKBH5 mitigates morphine tolerance, most likely through modulation of SGK1-associated immune signalling pathways. These findings suggest that the ALKBH5-m⁶A-SGK1 axis may participate in the epigenetic modulation of morphine tolerance and provides a promising molecular target for mitigating morphine tolerance.

Background and purpose: Lysine demethylase 1A (KDM1A; LSD1) plays anti-ferroptosis role and has been confirmed to be lowly expressed in Alzheimer disease (AD). This study explores whether LSD1 affects the progression of AD by regulating ferroptosis and related mechanisms involved.

Experimental approach: AD mice (APP/PS1 double transgenic) were injected with adeno-associated virus expressing LSD1 overexpression vector, or siRNA against leucine carboxyl methyltransferase 1 (LCMT1)/transcription factor EB (TFEB). SH-SY5Y cells were treated with Aβ1-42 to establish an AD cell injury model. The levels of lipid peroxidation and ferroptosis-related markers were tested to evaluate ferroptosis. The protein levels of LSD1, O-GlcNAcase (OGA), forkhead box transcription factor A2 (FOXA2), LCMT1, protein phosphatase 2A catalytic subunit alpha (PP2A) and TFEB were detected by western blot. The mRNA levels of LSD1 and OGA were assessed using quantitative real-time PCR. Interactions between targets were measured by ChIP-qPCR, DNA pull down, co-immunoprecipitation and dual-luciferase reporter assay.

Key results: LSD1 upregulation suppressed neuronal ferroptosis to attenuate AD progression in mice. Further, LSD1 overexpression alleviated Aβ1-42-induced cell injury by reducing OGA transcription and expression. OGA inhibited FOXA2 O-GlcNAcylation modification to promote its expression and transcriptional activity. Also, FOXA2 repressed LCMT1-mediated the activation of PP2A and TFEB. Furthermore, LSD1 alleviated AD process by inhibiting neuronal ferroptosis through the regulation of OGA/FOXA2/LCMT1/PP2A/TFEB axis.

Conclusions and implications: Overall, LSD1 restrained neuronal ferroptosis to alleviate the progression of AD by regulating LCMT1/PP2A/TFEB pathway via OGA-mediated FOXA2 O-GlcNAcylation modification, providing novel mechanistic insights into the deeper understanding of AD pathogenesis and the development of potential drug targets.

Cardiac remodelling and fibrosis after myocardial infarction or during chronic diseases, such as arterial and pulmonary hypertension or diabetes mellitus, continue to be the more important prognostic factors in determining survival, and so the search for effective anti-fibrotic interventions is an important target for research and therapy in cardiology. It has been suggested that compounds with anti-inflammatory and antioxidant properties (such as cannabinoids) may represent interesting therapeutic alternatives, due to their ability to influence pro-fibrotic signalling and inhibit pathological extracellular matrix deposition in the heart. This review describes the more important signalling pathways involved in cardiac fibrosis and some new concepts regarding the utility of cannabinoids and modulation of the endocannabinoid system (ESC) as therapeutic interventions against cardiac fibrosis. The studies presented in this review suggest that specific cannabinoid type 2 receptor activation and peripheral cannabinoid Type 1 receptor blockade appear particularly promising. The potential for the cardioprotective anti-fibrotic effects of cannabinoids and ECS modulators appears to lie in their high antioxidant and anti-inflammatory efficacy, which limits the progression of fibrotic lesions and restores normal regulation of molecular signalling pathways.

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.