- 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 Ghadzi, S. M. S., Karlsson, M. O., de Mello, V., Uusitupa, M., Kjellsson, M. C.The integrated glucose-insulin (IGI) model describes glucose and insulin after glucose administration in healthy individuals and patients with type 2 diabetes. The model, however, does not include disease progression (DP) from prediabetes to overt diabetes, which is driven by decreased insulin sensitivity and relative beta-cell failure. The objective of this study was to develop the IGI model to include the DP model for glucose and insulin in individuals with impaired glucose tolerance (IGT), with and without lifestyle intervention. Data of […]
- 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 […]
- by Li, Y., Cheng, Y.Chimeric antigen receptor (CAR) T-cell therapies exhibit complex cellular kinetics characterized by rapid expansion, contraction, and long-term persistence, often with substantial inter-individual variability, frequent below-quantification (BLQ) observations, and occasional influential data points. These features can destabilize inference under Gaussian residual assumptions and motivate robust, likelihood-based approaches that can jointly accommodate outliers and censoring. In prior work, we showed that combining Students t residuals with likelihood-based BLQ handling (M3 censoring) improves robustness in CAR-T cellular kinetics modeling; however, implementing Students t […]
- by Jia, X., Wang, T., Russo, D. P., Aleksunes, L. M., Xiao, S., Zhu, H.Hepatotoxicity remains a leading cause of drug attrition and post-marketing withdrawal, resulting from diverse and complex toxicity mechanisms. Traditional in vitro models can only capture a limited subset of toxicity pathways, and animal studies face translational and ethical limitations. Regulatory agencies have therefore promoted new approach methodologies, including human-relevant assays, omics technologies, and computational models to improve predictive toxicology and support evidence-based decision-making. However, most machine learning models for hepatotoxicity either rely solely on chemical structure or operate as black […]
- by Foyzun, T., Connor, M., Zaman, H., Kassiou, M., Kallinen, A., Santiago, M.IntroductionCannabinoid receptor-2 (CB2) is an emerging therapeutic target for chronic and inflammatory pain, cancer, and neurological disorders. Understanding the efficacy of CB2 ligands is crucial for future drug design and development. AimsWe aimed to establish a simple and robust system to control CB2 expression using a tetracycline-regulated mammalian expression system (T-REx), to enable application of the Black and Leff operational model to measure the operational efficacy ({tau}) of CB2 ligands. MethodsLigand-induced hyperpolarisation of AtT20 cells transfected with T-REx and human […]
- by Zhang, G., Gao, L., Ji, H., Zhang, T., Zhang, Y.ObjectiveThis study aimed to establish a green and efficient ultrasonic-assisted deep eutectic solvent (DES) extraction method for total flavonoids from Hemerocallis citrina Baroni (TFHC) and to elucidate its multi-target antidepressant mechanism using an integrated strategy of network pharmacology, molecular docking, and in vitro validation. MethodsAn ultrasonic-assisted DES extraction using choline chloride-ethylene glycol was optimized via response surface methodology. The TFHC extract was profiled by UPLC-ESI-MS/MS. A network pharmacology approach was employed to predict core targets and pathways of TFHC constituents […]
- by Kwon, J., Nkrumah-Elie, Y., Mavoyan, J. S., DB, M., AN, H., Shao, A.Nicotinamide riboside chloride (NR-Cl) has been studied predominantly by the oral route, while information regarding its toxicity following parenteral administration is limited. To characterize route-dependent acute toxicity and estimate median lethal doses (LD50), pharmaceutical-grade NR-Cl was evaluated following bolus intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration in female Sprague Dawley rats, in three independent studies. All studies were conducted using an adapted OECD Guideline 425 Up-and-Down procedure, modified for parenteral administration, in the absence of standardized route-specific OECD guidance. […]
- by Hamid, D., Auer, L., Mohr, S., Gazda-Miarecka, S., Salek, M., Kuehtreiber, H., Langoth-Fehringer, N., Pfleger, T., Klang, V., Mildner, M., Aigner, C., Sorgenfrey, D., Ankersmit, H. J., Dailey, L. A., Bello, G.APOSECTM, a complex mixture of secreted proteins, lipids, and extracellular vesicles from stressed peripheral blood monocytes, is currently in clinical trials for the treatment of chronic, poorly healing wounds. When applied to open wounds, 1 mL reconstituted APOSECTM lyophilisate is syringe-mixed with 3 g sterile hydrogel prior to administration. This study investigates the pharmaceutical performance of this novel administration system. A gel formulation (APOgel) was developed for terminal sterilisation in pre-filled syringes with post-sterilisation viscosity ([~]325-350{square}Pa*s at 1{square}s-1) comparable to […]
- by Marin-Jerez, E., Rueda-Carrasco, J., Melendez-Rodriguez, F., Partido-Borge, P., Tapia, E., Leibowitz, B. D., Parras, A.Mouse lifespan studies are slow and costly, limiting the number of interventions that have demonstrated robust anti-aging effects. This highlights the need for rapid early-stage screening tools capable of assessing both efficacy and potential side effects. Here, we present a short-term performance assay designed to rapidly profile functional benefits and early toxicity of longevity interventions in mice. Over an 8-week period, mice received one of five candidate anti-aging treatments: 17-estradiol, rapamycin + Smer28, berberine + resveratrol, sildenafil and pinealon. The […]
- by Shimochi, S., Hrovat, K., Sarwer, U., Bergara Muguruza, L., Alho, A., Laine, M., Otaka, A., Iwasaki, Y., Paatero, I., Gursoy, U. K., Makela, K., Savontaus, E., Salonen, J., Nakamura, M.Osteoporosis is a progressive skeletal disorder characterized by decreased bone mass and an increased risk of fracture. Current treatments are limited by adverse effects and poor long-term compliance, necessitating alternative therapeutic approaches. Tetracycline (TC) derivatives, which are traditionally used as antibiotics, have shown promise in modulating bone remodeling. In this study, the effects of TC and three TC derivatives–oxytetracycline (OC), doxycycline (DC), and minocycline (MC)–on osteoclast and osteoblast activities were investigated using in vitro human cell models and in vivo […]
- by Li, D., Guo, X., Zhao, Y., Li, C., Sun, Y., Lu, Y. f., Wang, Y., Liu, Y., Ma, B., Du, X.-D.Vancomycin-resistant enterococci (VRE) is one of the serious threat to global public health, with the diminishing effectiveness of antibiotics. There is an urgent need for novel strategies to control this multidrug-resistant bacterial infections. Here, our findings demonstrate that sublancin, a bacteriocin produced by Bacillus subtilis, exhibits intrinsic antibacterial activity and, more importantly, potentiates vancomycin, therapy restoring its efficacy against VRE. Using a series of in vitro assays, including fractional inhibitory concentration index, time-killing analysis, and resistance development assays, we show […]
- by Abou Choucha, F., Lopez-Goncalvez, R., Hermet, T., Mille, J., Guardini, L., Benkhedher, M., Lacoux, C., Gautier-Isola, M., Mograbi, B., Roux, J., Cottrez, F., Mari, B., Groux, H., Pasquier, C., Rezzonico, R., Vassaux, G.Exposure of cells or tissues to chemical compounds can be analyzed through transcriptomic signatures, which can be used to classify chemical agents. This information can also enrich Adverse Outcome Pathways (AOP). Transcriptional signatures have generally been obtained using "bulk" analysis, by which the global gene expression pattern of an entire tissue is determined. Although this approach has been useful in toxicology, some information is lost, especially when tissues containing multiple cell types are considered. With the advent of single-cell transcriptomics […]
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