Pharmacology Cambridge RSS Paper feed

Animal Model Exp Med. 2026 May 12. doi: 10.1002/ame2.70223. Online ahead of print.

ABSTRACT

Use of animals in biomedical research is still considered essential by many in academia, industry and regulatory authorities. Therefore, it is important that legal, governance and welfare procedures are in place to ensure that only necessary procedures using animals are carried out and that this occurs within a framework with animal welfare at its core. Animal research in the United Kingdom is conducted under the Animals (Scientific Procedures) Act 1986 and animal research in the United Kingdom has long been seen as a flag bearer for high quality-high welfare research. An example of the leading role taken in supporting animal welfare in research was establishment of the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) to support reducing the scale and impact of animal research. Here, we provide an overview of governance and licensing procedures of animal research in the United Kingdom, coupled with explanations of how excellent welfare underpins high quality research, and examine the development of new approach methodologies.

PMID:42117335 | DOI:10.1002/ame2.70223

Biochem Biophys Res Commun. 2026 May 4;821:153884. doi: 10.1016/j.bbrc.2026.153884. Online ahead of print.

ABSTRACT

Platelet activation is a key driver of in arterial thrombosis and myocardial infarction. Despite current anti-platelet therapies, mortality and morbidity from myocardial infarction remain high. Alternative anti-platelet therapies are needed that can reduce the risk of myocardial infarction without further increasing bleeding risk. Activated platelets rapidly diverge into distinct subpopulations. 'Procoagulant' platelets form through a mitochondria-dependent pathway. These procoagulant platelets expose phosphatidylserine (PS), which localises and amplifies the coagulation cascade leading to a large increase in thrombin generation and stable thrombosis. Procoagulant platelet formation may be a new target for anti-platelet therapies. A key regulatory step controlling progression to procoagulant platelets is opening of the mitochondrial permeability transition pore (mPTP). OSCP acts as a regulatory node for mPTP activity. Since mPTP opening regulates procoagulant platelet formation, we hypothesised that OSCP might also be a key regulatory node in platelets. OSCP is a target of the immunomodulatory benzodiazepine, Bz-423. In this study, we show that Bz-423 increased procoagulant platelet formation. This was associated with mitochondrial hyperpolarisation prior to platelet activation, and increased mPTP opening after activation. Cellular thermal shift assays (CETSA) showed that both Bz-423 and a structurally similar benzodiazepine, 4-chloro-dizaepam, bind OSCP in platelets. Despite this, only Bz-423 increased procoagulant platelet formation. Our findings indicate that Bz-423 promotes procoagulant platelet progression through a target distinct from OSCP.

PMID:42102671 | DOI:10.1016/j.bbrc.2026.153884

Nat Commun. 2026 May 7. doi: 10.1038/s41467-026-71902-1. Online ahead of print.

ABSTRACT

Apicomplexan parasites like Toxoplasma gondii harbor a divergent mitochondrial proteome, much of which remains uncharacterized despite its essentiality for parasite survival. One such essential pathway is ubiquinone (UQ) biosynthesis. Here, we characterize the UQ synthesis machinery in T. gondii and show that conserved enzymes, TgCoq3 and TgCoq5, are essential for growth and mitochondrial function, and associate in a multi-protein complex. Using proximity labeling and subcellular fractionation, approaches suited to detect low-abundance proteins, we identify TgCoqFMO, a FAD-dependent monooxygenase required for UQ synthesis. Unlike canonical eukaryotic systems that employ multiple monooxygenases to modify specific carbons on the UQ aromatic ring, TgCoqFMO catalyzes two distinct hydroxylation steps, an activity not previously reported in eukaryotes. Molecular docking and chemical screening identified TgCoqFMO inhibitors that impair tachyzoite growth and reduce bradyzoite viability. These findings reveal a divergent UQ biosynthesis pathway with fewer components in apicomplexans and establish TgCoqFMO as a promising antiparasitic target.

PMID:42098088 | DOI:10.1038/s41467-026-71902-1

Cell Rep. 2026 Apr 30;45(5):117335. doi: 10.1016/j.celrep.2026.117335. Online ahead of print.

ABSTRACT

Protein-based mosaic-8 nanoparticles displaying eight SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs) elicited broadly cross-reactive antibodies that could protect from zoonotic spillovers. Here, we extend the mosaic-8 concept to mRNA by encoding membrane-bound RBD quartets (four linked RBDs) as dual quartet RBD-mRNA and dual quartet RBD-EABR-mRNA, the latter leveraging ESCRT- and ALIX-binding region (EABR) technology for display on cell surfaces and secreted virus-like particles. Compared with protein-based mosaic-8, mRNA-encoded mosaic-8 induced equivalent or enhanced antibody breadth, neutralization potencies, and conserved epitope targeting, while eliciting enhanced T cell responses and more balanced IgG subclass profiles consistent with potentially superior Fc effector functions. Finally, systems serology-polyclonal epitope mapping (SySPEM) revealed distinct IgG-subclass-specific epitope signatures across mRNA, EABR-mRNA, and protein vaccines, demonstrating that the mode of antigen display can shape epitope recognition. Successful conversion of a multivalent protein vaccine to mRNA platforms informs the design of broadly protective vaccines and advances mosaic-8 toward clinical development.

PMID:42068547 | DOI:10.1016/j.celrep.2026.117335

J Chem Inf Model. 2026 Apr 28. doi: 10.1021/acs.jcim.5c02320. Online ahead of print.

ABSTRACT

Dispersion sensor (DspS) is a membrane-bound histidine kinase in Pseudomonas aeruginosa that senses cis-2-decenoic acid (CDA), a fatty acid signal regulating biofilm dispersion, motility, and virulence. However, its structural mechanism of signal transduction remains poorly defined. Here, we combined AlphaFold-Multimer modeling, multiple-replica accelerated molecular dynamics simulations, and Markov state modeling (MSM) to investigate the conformational dynamics of full-length dimeric DspS. Simulations focused on the cyclases/histidine kinase-associated sensory extracellular domain and transmembrane (TM) helices under four conditions: apo, dual-CDA-bound, dual arginine-to-alanine substitution, and single-CDA-bound. The apo form displayed a loosely packed TM2-TM2' helical arrangement, whereas dual CDA binding promoted a tightly crossed, signaling-competent configuration. In contrast, disruption of the conserved Arg residue weakened ligand anchoring and partially destabilized this packing. Under single-CDA binding, the DspS dimer adopted a primed state arising from asymmetrical ligand occupancy. In this state, the dimer bent toward the membrane interface, suggesting a distinct structural rearrangement relative to the apo and dual-bound forms. Such asymmetry may represent a mechanistic adaptation to fluctuating CDA levels, allowing graded receptor activation under dynamic environmental conditions. MSM analysis further revealed conformational plasticity, showing that full ligand occupancy stabilizes a network of metastable states and enables transitions within an active-like conformational ensemble. These findings provide the first atomistic view of DspS conformational switching, establishing a structural framework to study related histidine kinases and design antivirulence strategies targeting DspS-mediated biofilm control.

PMID:42050969 | DOI:10.1021/acs.jcim.5c02320

Commun Biol. 2026 Apr 26. doi: 10.1038/s42003-026-10110-5. Online ahead of print.

ABSTRACT

Cell-based assays are fundamental to G protein-coupled receptor (GPCRs) drug discovery. As the field strives to increase the use of physiological cell types with endogenous receptor expression, enhancing the sensitivity of simple-to-use assays unlocks new screening modalities. Here, we enhanced the responsivity of a Nuclear Factor of Activated T cells response element (NFAT-RE) reporter, by concatenating the IL-2 promoter-derived triplicate-binding sites, to produce three nano-luciferase reporter constructs termed NFAT 2X, NFAT 3X and NFAT 4X. Our enhanced reporters demonstrate larger maximal Fold Induction (FI) when co-expressed with both primarily and secondarily Gαq/11-coupled GPCRs. This pattern was maintained when stimulating endogenous GPCRs in a panel of immortalised cell lines (HEK293, HeLa, A549, and HEK293T) and allowed us to observe Sphingosine-1-Phosphate (S1P)-mediated signalling in primary human CD8+ T cells via CRISPR/Cas9 knock-in. Our NFAT-reporter T cells demonstrate the reporters potential for use in bi-allelic expression systems and primary cell types.

PMID:42034830 | DOI:10.1038/s42003-026-10110-5

Cell Metab. 2026 Apr 22:S1550-4131(26)00111-7. doi: 10.1016/j.cmet.2026.03.017. Online ahead of print.

ABSTRACT

Dietary protein promotes satiety and weight loss, yet how appetite-regulating neurons sense dietary protein remains poorly understood. Here, we show that Cacna1g, which encodes the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates neuronal leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of pro-opiomelanocortin (POMC) neurons in cultured neurons and brain slices, thereby suppressing the anorectic response to hypothalamic leucine in vivo. Genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, leucine binds a hydrophobic pocket of Cav3.1 and lowers its threshold for voltage-dependent activation. Finally, pharmacological activation of mediobasal hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates responses to anorectic agents, including liraglutide. Together, these findings establish hypothalamic Cav3.1 as a neuronal leucine sensor and nominate it as a tractable target for anti-obesity therapy.

PMID:42025169 | DOI:10.1016/j.cmet.2026.03.017

Br J Biomed Sci. 2026 Apr 7;83:15884. doi: 10.3389/bjbs.2026.15884. eCollection 2026.

ABSTRACT

BACKGROUND: The G protein-coupled receptor 68 (GPR68) detects variations in extracellular pH, and has potential roles in homeostasis and responses to ischaemia and inflammation within different organs, including the gastrointestinal tract. However, in the human colon the distribution of GPR68 remains unclear. We examined the localization and density of GPR68 within the ascending (AC) and descending (DC) human colon from younger and older adults.

METHODS: Macroscopically normal AC and DC were obtained from patients undergoing lower bowel cancer resection (aged 22-91 years; grouped into younger (≤60 years) and older (≥67 years) populations). Immunolabelling was performed using formalin-fixed, paraffin-embedded sections and antibodies against GPR68, protein gene product 9.5 (PGP9.5) and calretinin to identify the presence and density of GPR68-immunoreactive (IR) expressing cells.

RESULTS: Ageing did not change the density of total PGP9.5-IR enteric neuronal fibres in the AC or DC. For the myenteric plexus (MP) of both age groups, the densities of calretinin-IR neurons were similar in both the AC (younger: 1.2 ± 0.3 × 10-3; older: 0.9 ± 0.2 × 10-3 per mm2 plexus) and DC (1.4 ± 0.2 × 10-3; 1.3 ± 0.3 × 10-3 per mm2 plexus), but reduced in the mucosa of older adults for both AC (respectively, 9.8 ± 0.5 vs. 3.2 ± 0.1/pixel) and DC (11.5 ± 0.9 vs. 7.4 ± 0.3/pixel). Similar reduction of calretinin-IR enteric neurons was found in the SMP of AC but not clearly in the DC in the older adults. GPR68 was widely expressed in the mucosa, circular muscle and myenteric plexus of both the AC and DC. The density of GPR68-IR in the muscle and myenteric plexus was similar in both age groups, but smaller in the mucosa of older adults for both AC and DC.

CONCLUSION: GPR68 is widely distributed within the enteric nervous system of the human colon, with potential roles for GPR68 suggested in the muscle and MP, and in the functions of calretinin-IR neurons within the mucosa. Further, the concomitant loss of GPR68 and calretinin-IR neurons in the mucosa of older adults suggests selective vulnerability of mucosal sensory and homeostatic mechanisms of the ageing colon.

PMID:42022898 | PMC:PMC13095668 | DOI:10.3389/bjbs.2026.15884

Pain Rep. 2026 Apr 20;11(3):e1446. doi: 10.1097/PR9.0000000000001446. eCollection 2026 Jun.

ABSTRACT

INTRODUCTION: Abdominal pain is a significant burden for those living with inflammatory bowel disease (IBD), representing a major unmet clinical need due to the scarcity of effective therapeutic options. The G protein-coupled receptor, protease-activated receptor 2 (PAR2), has emerged as a promising therapeutic target for visceral pain management in IBD.

OBJECTIVES: We set out to determine signaling mechanisms deployed by PAR2 in the lumbar splanchnic nerve and whether inhibiting PAR2 with the mouse monoclonal antibody (mAb), PAR650097 (mPAR650097) provided therapeutic benefit in dextran sulfate sodium (DSS)-induced colitis.

METHODS: We first used ex vivo electrophysiological recordings of mouse lumbar splanchnic nerve to determine how stimulation of PAR2 alters afferent activity and the intracellular signaling mechanisms involved. Second, we used the DSS model of colitis in mice and determined how mPAR650097 altered disease activity, behavior, colon histology, and the activity of nociceptive circuitry.

RESULTS: Protease-activated receptor 2 stimulation in the colon activated visceral afferent fibers and sensitized them to mechanical and chemical stimuli. We found that endosomal internalization and protein kinase A/C signaling mediate both activating and sensitizing effects of PAR2 in visceral pain. We further show that inhibiting PAR2 with the mAb mPAR650097 reduces DSS-induced colitis severity and pain. mPAR650097 also reduced several colitis-induced pain correlates at key points along the pain-signaling axis, including peripheral nociceptive neuron signaling and sensitivity, expression of proinflammatory mediators, spinal cord signaling, and, fundamentally, behavior.

CONCLUSION: These findings illustrate that mAb inhibition of PAR2 represents a promising approach to provide relief from abdominal pain in those living with IBD.

PMID:42021789 | PMC:PMC13098787 | DOI:10.1097/PR9.0000000000001446

Neurosci Lett. 2026 Mar 18:138585. doi: 10.1016/j.neulet.2026.138585. Online ahead of print.

ABSTRACT

There is a pressing need for effective alternatives to opioid analgesics, the development of which requires the identification of novel anti-nociceptive drug targets. Here, we have further investigated the anti-nociceptive properties of a GPR35 agonist, cromolyn, in an in vitro model of inflammatory sensitisation. We used ratiometric Ca2+ imaging of cultured sensory neurons to examine the effect of cromolyn on prostaglandin E2 (PGE2)-mediated sensitisation of the pro-nociceptive ion channel, transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The sensitisation of TRPV1 by PGE2 was inhibited by cromolyn in a GPR35-dependent manner. These observations provide further evidence in support of an anti-nociceptive role for GPR35, highlighting the potential use of GPR35 agonists as analgesics.

PMID:41862074 | DOI:10.1016/j.neulet.2026.138585

Nat Commun. 2026 Feb 27. doi: 10.1038/s41467-026-70020-2. Online ahead of print.

ABSTRACT

Rank signaling regulates mammary gland development and epithelial differentiation. While Rank is expressed in both basal and luminal cells, its basal-specific role is unclear. Here, using inducible basal-specific Rank expression and lineage tracing, we show that Rank signaling regulates basal cell identity in postnatal mammary glands. Increased basal Rank activity disrupts basal and luminal identities, causing aberrant luminal-like differentiation, lactation defects, and premalignant lesions composed of hybrid basal-derived cells that progress to basal and luminal adenocarcinomas. Conversely, Rank loss reduces tumor formation and also impairs cell identity. Mechanistically, proteomic, transcriptomic, and chromatin analyses reveal that Rank activation drives epigenetic remodeling, leading to basal identity loss and tumor initiation. A basal Rank gene signature correlates with ductal carcinoma in situ recurrence, as well as poor outcomes in luminal breast cancers. Thus, basal Rank-driven lineage infidelity promotes pre-invasive lesions and transition to invasive breast cancer in females.

PMID:41760656 | DOI:10.1038/s41467-026-70020-2

JACS Au. 2026 Jan 20;6(2):1102-1117. doi: 10.1021/jacsau.5c01514. eCollection 2026 Feb 23.

ABSTRACT

Small molecule activators of protein phosphatase 2A (PP2A), hereafter SMAPs, have attracted substantial interest for their potential to inhibit cancer cell proliferation by targeting PR65, the scaffold subunit of the PP2A heterotrimer. PR65 is a uniquely flexible and stable molecule composed of 15 tandem HEAT (Huntingtin, Elongation factor 3-PP2A-TOR1) repeats. We characterized the binding sites and interactions of two SMAPs ATUX-8385 and DT-061 with PR65 and evaluated the effects on PR65 structural dynamics using docking and molecular dynamics simulations. We initiated SMAP-bound PR65 simulations starting from two binding sites: S1, determined by cryo-electron microscopy for DT-061 bound to PP2A, on the inner helices of the HEAT repeats 2 and 3 (2i and 3i); and S2, predicted by docking of ATUX-8385 onto PR65, on 4i and 5i and outer helices 5o and 6o consistent with footprinting experiments. S2 proved to be a stable site for both SMAPs when simulations were initiated at S2. However, neither DT-061 nor ATUX-8385 demonstrated stable binding to S1. DT-061 rapidly dissociated from S1 to settle instead at a neighboring site S4 overlapping with our previously identified S3 for PR65 in extended form, suggesting that binding to S1 may be a two-step process: an initial binding to PR65 alone, either to S3/S4 or S2, followed by movement to S3/S4, and then an induced relocation to S1 upon complexation with the regulatory and catalytic subunits. Targeted in silico mutagenesis showed that mutations at S2 and S4 destabilized binding of SMAP to PR65 (subunit). Heterotrimeric PP2A simulations showed that S3 and S4 bindings were not persistent upon complexation. Together, these results corroborate our findings. Furthermore, this preferentially stabilized a relatively extended PR65 conformation that would accommodate, if not promote, the assembly of the catalytic and regulatory subunits to prompt the activation of the trimeric phosphatase.

PMID:41755833 | PMC:PMC12933302 | DOI:10.1021/jacsau.5c01514

Nat Cardiovasc Res. 2026 Feb 6. doi: 10.1038/s44161-026-00776-9. Online ahead of print.

ABSTRACT

Myocardial injuries lead to cardiomyocyte loss and heart failure. Endogenous glucocorticoids, via the glucocorticoid receptor (GR), limit cardiomyocyte regeneration. Here we show that glucocorticoids suppress mammalian (murine) cardiomyocyte proliferative response to regenerative growth factors and cytokines. GR activation in neonatal cardiomyocytes upregulated MAPK-ERK inhibitors ERRFI1 and DUSP1. Using neuregulin 1 as a model, we demonstrated that glucocorticoids inhibit growth-factor-induced ERK activation, nuclear translocation and transcriptional output. Errfi1 and Dusp1 knockdown restored growth-factor-induced proliferation of glucocorticoid-exposed cardiomyocytes. Cardiac expression of DUSP1 and ERRFI1 increased postnatally, coinciding with regenerative capacity decline. In juvenile and adult cardiomyocytes, regenerative growth factors failed to induce the MAPK-ERK pathway and proliferation; however, DUSP1 inhibition restored these responses. GR antagonism enhanced growth-factor-induced cardiomyocyte protection, proliferation and cardiac function after adult myocardial injury. These findings reveal the emergence of a postnatal systemic brake on cardiomyocyte proliferative response to growth factors and support GR inhibition as a strategy to enhance growth-factor-based regenerative therapies.

PMID:41652035 | DOI:10.1038/s44161-026-00776-9

Science. 2026 Feb 5;391(6785):553-554. doi: 10.1126/science.aee5778. Epub 2026 Feb 5.

ABSTRACT

DNA origami scaffolds displaying HIV antigens stimulate focused antibody responses in mice.

PMID:41643031 | DOI:10.1126/science.aee5778