- by Murata, I., Kobayashi, J., Ishihara, S., Iyi, N.Crush syndrome (CS) is characterised by ischaemia/reperfusion-induced rhabdomyolysis, leading to systemic inflammation and high mortality. Building on our previous findings that intravenous nitric oxide (NO) donors improve survival in this condition, we investigated the therapeutic efficacy of inhaled NO delivered via a portable, controlled-release device in an experimental rat model of CS. Anaesthetised rats underwent bilateral hindlimb compression using rubber tourniquets for 5 h, followed by reperfusion. Among the various inhalation conditions tested, administration of NO (160 parts per million) […]
- by Chen, C., Zhao, Y., Du, F., Liu, R., Zheng, X., Wu, S., Wang, Y., Qiu, F., Chen, L., Chen, R., Li, F., Gong, L., Long, Y.Stimulator of interferon genes (STING) agonists and derivative molecules have been extensively developed for tumor immunotherapy. However, systemic exposure toxicity risks have constrained clinical trial progression and even threatened patient lives. Currently, systematic toxicity assessments for STING agonists remain lacking, with the mode of action for major organ injury yet to be elucidated. Here, we focused on STING agonist-induced lung injury, revealing that systemic administration of STING agonists caused pulmonary hemorrhage, inflammatory alterations, and respiratory dysfunction. Through single-cell RNA sequencing […]
- by Sun, W., Hu, B., Li, D., Qian, Y., Huang, C., WANG, N.Background: Current heart failure (HF) biomarkers (e.g., BNP/NT-proBNP) have limitations in specificity and performance in HF with preserved ejection fraction (HFpEF). Circulating microRNAs (miRNAs) are promising novel biomarkers. This study aimed to comprehensively evaluate the diagnostic stability of circulating miRNAs for HF, identify novel candidates, and prioritize them for clinical translation. Methods: We conducted a systematic review and meta-analysis. PubMed, Embase, and Cochrane Central were searched from inception to March 2025. Studies comparing miRNA expression in HF versus control groups […]
- by Saini, A., Gallo, J.The current investigation introduces single-cell physiologically-based pharmacokinetic (scPBPK) models to gain insight into drug disposition at the cellular scale. The transition from standard PBPK (sPBPK) models to scPBPK models required depiction of expression-dependent (ED) processes, such as drug metabolism or membrane transport. ED processes utilize weighting functions – a defined or data-driven distribution – that yield heterogeneity in individual cell kinetics. Two scPBPK model examples are provided, one involving a drug (AZD1775) subject to 3 ED blood-brain barrier transport processes, […]
- by Chang, N., Moore, H. P., Himeda, C. L., O'Brien, T. E., Thomas, W., Jones, T. I., Jones, P. L.Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic dysregulation of the disease locus, leading to pathogenic misexpression of DUX4 in skeletal muscle. Thus, most FSHD therapeutic approaches target DUX4. Our previous study identified the chromatin remodeling factor BAZ1A (bromodomain adjacent to zinc finger domain protein 1A) as a promising target for therapeutic development. Here we used an artificial intelligence-based screening pipeline to identify molecules predicted to bind the BAZ1A bromodomain, and validated hit compounds using FSHD-specific assays in FSHD myocytes. […]
- by Massa, J., Hense, J., Gangnus, T., Gozzi, M., Bulk, E. E., Burckhardt, B., Duefer, M., Schwab, A., Koch, O.The ion channel KCa3.1 plays a role in immune regulation, red blood cell function, and is linked to numerous types of cancer. Various animal toxins, such as maurotoxin, bind to the extracellular side of KCa3.1, providing a potential starting point for inhibitor development. We report in this work the discovery of a novel, small-molecule inhibitor, with a micromolar IC50, which was specifically designed to target plasma-membrane KCa3.1 channels from the extracellular side. This compound can serve as a starting point […]
- by Narra, N., Richards, A. M., Earl, C. C., Cox, A. D., Dahl, R., Koss, W. A., Goergen, C. J.Progressive cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Dysregulation of calcium handling has been implicated in cardiomyopathy progression in DMD. Here we describe a therapeutic approach to improve calcium homeostasis in a mouse model of DMD using the novel therapeutic NDC-1171, which is a positive allosteric modulator of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump. We synthesized NDC-1171 and treated 4-week-old D2.mdx mice (n=9) via oral gavage. A group of D2.mdx mice (n=9) and a […]
- by Kuncewicz, K., Upadhyay, S., Zhu, R., Duan, H., Gabr, M.Immune checkpoint therapies have transformed immunotherapy but remain dominated by biologic agents characterized by prolonged receptor occupancy and limited pharmacologic controllability. Synthetic modalities capable of targeting protein-protein interaction interfaces while enabling tunable immune regulation remain largely unexplored. Here, we report an AI-guided strategy for discovering cyclic peptide antagonists of the costimulatory receptor CD28. The lead peptide, CIP-3, binds the CD28 extracellular domain with nanomolar affinity and competitively disrupts CD28-ligand interactions. In primary human immune systems, CIP-3 suppresses CD28-dependent T-cell activation […]
- by Lyons, K., Leonard, D., McSharry, L., Martindale, M., Collier, B., Vitkauskaite, A., Dunbar, J. P., Dugon, M. M., Healy, K.Historically, venom potencies have been assessed using measures of lethality, such as the median lethal dose (LD50). However, venoms may be selected primarily for their ability to rapidly incapacitate rather than cause mortality, meaning LD50 may not capture the efficacy of venoms in an ecological and evolutionary context. To capture this context, recent studies have adapted measures that assess venoms ability to rapidly incapacitate, such as the median effective dose (ED50). However, while ED50 values are expected to provide a […]
- by Nanna, V., Paternoster, C., Bartocci, A., Alberga, D., Abate, C., Lattanzi, G., Mangiatordi, G. F.The sigma-1 receptor (S1R) is an endoplasmic reticulum transmembrane protein implicated in a wide range of physiological and pathological processes, including neurodegeneration, cancer, and pain modulation. Although X-ray crystallography has revealed S1R as a trimeric assembly with a distinctive triangular architecture, the dynamic behavior of this oligomeric state and its modulation by ligands and membrane composition remain poorly understood. In particular, agonists and antagonists have been experimentally proved to differentially regulate S1R oligomerization although the underlying molecular mechanisms are still […]
- by Benfeito, S., Alves, C., Lima, C., Borges, F., Sequeira, L., Cagide, F., Rocha, T.Fungal pathogens are an escalating global public health concern, particularly in the context of invasive and opportunistic infections. Cryptococcosis, primarily caused by Cryptococcus neoformans var. grubii, can manifest as acute, subacute, or chronic disease, affecting multiple organs and frequently leading to life-threatening meningitis in immunocompromised individuals. Given the limited antifungal therapeutic strategies and the emergence of resistance and toxicity-related constraints, the development of novel anti-cryptococcal agents remains an urgent priority. In this study, a library of innovative hybrids (5a-f) based […]
- by Bartlett, J., Robinson, E.Voluntary ingestion is a refined method for substance administration that can replace oral gavage in rats and mice. It requires no physical restraint and has no associated risks of adverse effects, resulting in improved welfare and reduced distress for both animals and research staff. This method has been shown to be effective for a variety of compounds but is still not widely used due to concerns about accuracy and reliability. One potential issue is aversion to the taste of the […]
- by Blount, A., Sutton, L.Targeting the kappa opioid receptor (KOR) system has emerged as a potential alternative to current analgesics, however, advancing the therapeutic development of KOR requires further elucidation of its intracellular signaling events and modulators. Among these intracellular modulators, Regulators of G protein signaling (RGS) proteins act as key modulators of GPCR signaling to shape nociceptive circuits and influence pain processing. Despite this, the molecular diversity of RGS proteins that shape KOR signaling and its behavioral consequences remains largely unexplored. Here we […]
- by Stokes, L., Stockin, K. A., Stevenson, G., Dearaujo, J., Saltre, F., Peters, K. J.Per- and polyfluoroalkyl substances (PFAS) are globally recognised as emerging contaminants of concern due to their persistence, toxicity, endocrine-disrupting and immunosuppressive effects. Because of their extensive industrial use, PFAS are now widespread across ecosystems and accumulate in marine environments. Despite their ubiquity, the extent and drivers of PFAS contamination remain poorly characterised, particularly in marine systems. Odontocetes (toothed whales) are effective bioindicators of marine pollution, integrating contamination across regions, time, and trophic levels. Here, we present the first global assessment […]
- by Cho, S., Gabr, M.Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimers disease (AD). VG-3927, the first clinical-stage small-molecule TREM2 agonist, has been proposed to function as a transmembrane molecular glue and positive allosteric modulator (PAM). Whether it directly engages the extracellular ligand-recognition surface of TREM2 remains unknown. Here, we used a deep learning-based blind docking algorithm to map potential VG-3927 binding sites across TREM2 and identified a binding site within the ectodomain […]
- by Rajbanshi, B., Guruacharya, A.First-in-human (FIH) dose selection for monoclonal antibodies (mAbs) typically relies on deterministic allometric scaling but lacks formal uncertainty quantification. While Bayesian methods have been widely applied in population PK modeling and dose individualization, their use for propagating uncertainty through allometric scaling in mAb FIH dose selection has not been systematically explored. This is a critical limitation for molecules with narrow therapeutic windows, such as CNS-targeted mAbs, where the blood-brain barrier restricts IgG penetration to [~]0.1-0.3% of plasma concentrations, requiring high […]
- by Bhavsar, A. P., Zandi, Z., Hartley, B., Bassiouni, W., DuVal, M. G., Luo, S., Spavor, M. J., Allison, W. T., Julien, O., Schulz, R.Matrix metalloproteinases (MMPs) are rapidly expressed and activated in response to oxidative stress and contribute to various pathological conditions. Cisplatin is a highly effective chemotherapeutic agent; however, its clinical use is limited by its associated permanent hearing loss (ototoxicity). While cispwlatin-induced oxidative stress and inner ear cell death are well-established, the contribution of MMPs remains unclear. In this study, we demonstrate that cisplatin exposure triggers activation of MMP-2 and MMP-9 and expression of an intracellular N-terminal-truncated isoform of MMP-2 in […]
- by Li, Y., Cheng, Y.BackgroundReliable population pharmacokinetic (PopPK) parameter estimation can be compromised by outliers under Gaussian residual error models. A common mitigation strategy is post hoc filtering based on conditional weighted residuals (CWRES); however, this approach can be insensitive due to model "masking" driven by variance inflation. Practical barriers to implementing robust likelihoods in standard software have motivated interest in computationally simpler exponential-tail alternatives such as the Laplace and exponential power distribution (EPD). MethodsWe implemented a one-compartment PopPK model using a custom likelihood […]
- by Li, Y., Cheng, Y.Chimeric antigen receptor (CAR) T-cell therapies undergo rapid in vivo expansion followed by contraction and variable long-term persistence after a single infusion, yielding cellular kinetic (CK) profiles that differ fundamentally from conventional small-molecule and biologic pharmacokinetics. Piecewise, phase-based CK models are widely used, but discontinuous switching and constant expansion assumptions can create numerical instability around the transition window and bias the characterization of early expansion and near-peak behavior. Building on our prior saturable expansion framework (Vmax/Km), we advanced CAR-T CK […]
- by LI, Y., CHENG, Y.Spatial heterogeneity in drug distribution, particularly within solid tumors, can compromise target engagement and drive therapeutic failure in oncology, yet it is rarely represented in population pharmacokinetic (PopPK) analyses. Standard empirical compartmental or semi-mechanistic models assume "well-stirred" tissues, and physiologically based pharmacokinetic (PBPK) models focus on organ-level distribution; neither framework directly captures intra-tumoral drug concentration gradients. Reaction-diffusion PDEs provide a mechanistic representation of penetration, spatial gradients, and washout, but routine implementation in NONMEM has been limited by operational complexity in […]
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