British Journal of Pharmacology最新文献

Background and purpose: Human adenovirus (HAdV) causes respiratory or gastrointestinal tract infections depending on the virus subtype. While HAdV infections are generally self-limiting in immunocompetent people, they can result in significant morbidity and mortality in immunocompromised adults and children. Due to the limited availability of effective therapeutic options, there is an urgent need for novel therapeutics to combat HAdV infection and mitigate its severity.

Experimental approach: Here, we have repurposed the clinically well-used antifungal, itraconazole, to control HAdV infection. We tested the antiviral potential of the itraconazole and the mTOR inhibitor Ku-63794 on the production of infectious HAdV in A549 and Caco-2 cells as well as human intestinal organoids (HIOs). Additionally, we evaluated the benefit of a combination of these host-directed drugs with the direct-acting antiviral brincidofovir.

Key results: Pharmacological treatment with itraconazole significantly reduced virus titres in different in vitro models, including HIOs. Treatment with itraconazole impairs HAdV entry by entrapping incoming virus particles in endolysosomes and by promoting autophagy in HAdV-infected cells. Moreover, combining itraconazole with brincidofovir, a cidofovir derivative currently under clinical evaluation for anti-HAdV applications, demonstrated a synergistic effect in reducing HAdV titres.

Conclusion and implications: Given the gastrointestinal toxicity associated with brincidofovir, its combination with the host-directed drug itraconazole allowed lower brincidofovir doses to be used to decrease HAdV titres, thereby minimizing adverse drug effects while maintaining antiviral efficacy.

Zhou, F., Xia, J., Liu, Y., He, W., Zhang, H., Keavney, B. D., Zi, M., Nguyen, B. Y., A. Mohamed, T. M., Miller, J. M., Abouleisa, R. R.E., Hille, S. S., Cartwright, E. J., Müller, O. J., Xu, H., Butterworth, S., & Wang, X. (2025). Stabilisation of PRCP by deubiquitinase-targeting chimera (DUBTAC) to replenish autophagy for ameliorating pathological cardiac hypertrophy. British Journal of Pharmacology, 182(21), 5317–5339. https://doi.org/10.1111/bph.70094

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Background and purpose: Guanylate cyclase-C (GC-C) is the receptor for endogenous (uro)guanylin peptides, bacterial toxins and pharmacological analogues. Receptor activation leads to intestinal fluid loss, but also activates an antiproliferative pathway and is a promising target in colorectal cancer therapy. The present study delineates the molecular mechanisms that regulate the intensity of the anion secretory response (ASR) to GC-C activation in the different segments of the murine ileocolon.

Experimental approach: To assess the ASR to the guanylin analogue linaclotide, isolated mucosa from the different segments of the ileocolon of cGMP-dependent kinase II (cGKII)-deficient and WT mice were studied electrophysiologically in Ussing-chambers. The mucosal expression pattern of different phosphodiesterases (PDEs) was measured by RT-PCR.

Key results: The ASR to linaclotide and 8-pCPT-cGMP was strongly dependent on the presence of cGKII in the ileum and proximal colon, but not in the mid and distal colon, where cGKII expression is low. The inhibition of cGMP-sensitive PDE3 completely prevented the linaclotide-induced ASR only in the mid and distal colon, demonstrating that GC-C dependent ASR occurs via an increase in cAMP in these segments, mediated by the cGMP-induced inhibition of PDE3. In addition, the cGMP-specific PDE9 was highly expressed in the distal colon, and its inhibition strongly enhanced the ASR to linaclotide.

Conclusions and implications: GC-C activation leads to CFTR-mediated ASR in all segments of the intestine. In the mid and distal colon ASR is strongly reduced by the low cGKII and high PDE9 expression, with the CFTR channel being activated via cAMP-mediated phosphorylation.

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: Alarming trends show that vaping e-cigarettes containing synthetic cannabinoid receptor agonists, such as JWH-018, is increasing among youth. However, the effects of these trends are unclear in both sexes. We therefore characterized the neuropharmacological effects of adolescent JWH-018 inhalation in male and female rats.

Experimental approach: Adolescent rats inhaled passively JWH-018 vapour (0.3 or 0.6 mg·ml^-1 qd) for 21 days. During vapour exposure, JWH-018 and main metabolite plasma levels, body weight, locomotion and ultrasonic vocalizations were measured at different time points. During drug-free period, behavioural (withdrawal signs, anxiety and repetitive-like behaviour) and microdialysis (NAc shell/mPFC dopamine responsiveness to intraoral chocolate, taste reactivity) studies were performed 24 h and 7 days after last JWH-018 inhalation, respectively.

Key results: Repeated adolescent JWH-018 inhalation induced sex-dependent effects with (i) higher plasma levels in males; (ii) increased body weight gain and withdrawal signs in females; (iii) transient hypolocomotion in females and dose-dependent biphasic locomotion in males; (iv) higher taste aversion in male; (v) sex- and dose-dependent adaptive changes of NAc shell and mPFC dopamine to single/repeated chocolate exposure in early adulthood, as follows: in the NAc shell, either low or high dose decreased dopamine sensitivity to chocolate in males, low dose abolished habituation whereas high dose blunted dopamine responsiveness in females; in the mPFC, the low dose blunted responsiveness in male and induced habituation in females while the high dose induced habituation only in males.

Conclusion and implications: Using highly translational models, we showed that the impact of adolescent JWH-018 inhalation differs between sexes.

Background and purpose: 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a psychostimulant with entactogenic properties and known to induce arousal and euphoria. As an amphetamine derivate, MDMA acts on the monoamine systems in the brain and stimulates release of dopamine (DA), noradrenaline (NA) and serotonin (5-HT), yet their individual contributions in driving arousal and euphoria remain controversial.

Experimental approach: We studied the effects of central 5-HT deficiency and compared the behavioural responses evoked by MDMA (10 mg kg^-1) in female and male Tph2^-/- knockout and Tph2^+/- heterozygous rats, with no or reduced central 5-HT, respectively, to Tph2^+/+ wild-type (WT) littermate controls. As markers for arousal and euphoria, we assessed psychomotor activation and 50-kHz ultrasonic vocalisations (USV), respectively.

Key results: Central 5-HT deficiency caused by genetic ablation of Tph2 blocked MDMA-induced psychomotor activation and 50-kHz USV. Whereas MDMA evoked a substantial increase in psychomotor activation in Tph2^+/- heterozygous rats and Tph2^+/+ WT littermates, no such prominent response was seen in Tph2^-/- knockout rats. Moreover, MDMA evoked a mild increase in 50-kHz USV in Tph2^+/+ WT littermates but not Tph2^+/- heterozygous and Tph2^-/- knockout rats. Genotype effects were robust and typically seen in both sexes.

Conclusions and implications: MDMA does not induce a prominent increase in psychomotor activation and 50-kHz USV in Tph2-deficient rats lacking 5-HT in the central nervous system. This suggests that the robust induction of arousal and euphoria by MDMA in intact rats is not driven by the release of DA or NA, but depends on central 5-HT.

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.

UK Biobank is a large-scale, prospective study with extensive genetic and phenotypic data on half a million individuals. Volunteers, aged between 40 and 69 years, were recruited between 2006 and 2010 from the general population of the United Kingdom. At recruitment, participants completed a series of questionnaires on a range of factors (including lifestyle and medical history), physical measurements were taken and biological samples were collected for long-term storage. Large-scale assays have been undertaken (including biochemical assays, genotyping, whole exome and whole genome sequencing, as well as proteomics and metabolomics) with potential for further assays to be performed on stored samples in the future. The participants provided consent for linkage to their health-related records to identify health outcomes over time. The UK Biobank study, with its vast collection of genetic data, has enabled researchers worldwide to identify new drug targets for common diseases of middle and older age, and progress towards precision medicine. As the UK Biobank resource matures, its value to health-related research will continue to grow. Thousands of researchers worldwide are actively using UK Biobank data to improve our understanding of the prevention, diagnosis and treatment of a wide range of diseases.