- by De Vass Gunawardane, S., Epitawala Arachchige, O. V., Wijerathne, S. K., Punyasiri, P. A. N., Murugananthan, A., Samarakoon, S. R., Senathilake, K. S.A cassane diterpene, 6{beta}-cinnamoyl-7-hydroxyvouacapen-5-ol (6{beta}CHV), isolated from Caesalpinia pulcherrima, has emerged as a promising anticancer drug lead with reported Wnt/{beta}-catenin pathway inhibitory activity and in vivo safety. The present study reports the in vivo pharmacokinetics and tissue distribution of 6{beta}CHV in Wistar rats following a single oral dose of 200 mg/kg. A reproducible RP-HPLC-UV method was developed and validated for quantifying 6{beta}CHV in rat plasma and tissues. Chromatographic separation was achieved using a gradient elution of methanol and water. The […]
- by Chetverikov, N., Szanti-Pinter, E., Jurica, J., Vodolazhenko, M., Budesinsky, M., Zima, V., Svoboda, M., Dolejsi, E., Janouskova-Randakova, A., Urbankova, A., Jakubik, J., Kudova, E.Steroid-based fluorescent-quencher probes now enable real-time, residue-level mapping of previously inaccessible cholesterol-binding sites on G-protein-coupled receptors. We designed Tide Quencher 1 (TQ1) conjugated steroids that target two distinct peripheral sites on the M1 muscarinic receptor. One near the extracellular N-terminus and another adjacent to the intracellular C-terminus. Using pregnanolone glutamate as a versatile scaffold, we synthesised a library of probes varying in C-3 linker length ({gamma}-aminobutyric acid vs. L-glutamic acid) and C-3/C-5 stereochemistry (3/3{beta}/5/5{beta}). Fluorescence-quenching assays with CFP-tagged receptors revealed […]
- by Garcia-Cabrerizo, R., Bergas-Cladera, P., Colom-Rocha, C., Garcia-Fuster, M. J.The use of neuromodulation techniques for the treatment of alcohol use disorder is receiving increasing attention, especially non-invasive approaches, such as repetitive transcranial magnetic stimulation or transcranial direct current stimulation, while the hypothetical use of electroconvulsive therapy remains unexplored. Given our experience inducing electroconvulsive seizures (ECS) for therapeutic purposes in psychopathology rodent models, we evaluated the role of ECS on reducing the increased voluntary ethanol consumption caused by adolescent ethanol exposure in our validated preclinical model. Rats were treated in […]
- by Andersson, L., Wesolowski, P. A., Jahrstorfer, L., De Rosa, A., Heger, T., Neuman, V., Sieradzan, A. K., Wales, D. J., Kozielewicz, P.G protein-coupled receptors rely on dynamic conformational changes to coordinate G protein activation and recruitment of regulatory transducers such as G protein-coupled receptor kinases and {beta}-arrestins. The chemotactic receptor GPR183 has been implicated in a context-dependent role in hematological malignancies. Here, we investigated the impact of A338V mutation located within the C-terminal tail of GPR183. This mutation is associated with acute myeloid leukaemia. Using bioluminescence resonance energy transfer-based assays in HEK293A cells, we assessed receptor-proximal signaling events. The A338V variant […]
- by Rajbanshi, B., Iqbal, K., Guruacharya, A.Assessing whether a preclinical drug candidate will work is not a prediction problem but a reasoning problem. The same numerical output warrants different interpretations depending on the target and therapeutic context. CNS drug development presents the most demanding instance of this reasoning problem. For example, a compound must cross the blood-brain barrier, resist efflux transport, and achieve adequate receptor occupancy at a dose that clears safety margins. The constraints interact with each other in a web that needs careful interpretation. […]
- by Kheder, S., Krkoska, M., Mihalic, F., Kobar, K., Andrysik, Z., Bräutigam, L., Lindström, S., Berman, J. N., Lane, D. P., Lama, D., Kannan, P.Measuring the activity of the tumor suppressor p53 in living systems is essential for understanding its dysregulation in cancer and other conditions, such as aging and diabetes. Zebrafish (Danio rerio) are a powerful vertebrate model that enable such studies, due to the evolutionary conservation of p53 structure and function. However, p53 activity in zebrafish has mainly been assessed using pharmacological methods that induce DNA damage or have off-target effects, making it difficult to isolate p53-specific responses from broader stress responses. […]
- by Nyimanu, D., Chakraborty, A., Parnell, S., Wallace, D., Yu, A.BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder marked by numerous renal cysts that impair kidney function, with about half of affected individuals progressing to kidney failure by midlife. Patients exhibit reduced circulating apelin, a ligand of the apelin receptor, known to regulate cardiovascular function including hypertension. We tested whether diminished apelin signaling contributes to cystogenesis and if exogenous apelin receptor activation can improve disease outcomes. MethodsPlasma samples from age- and sex-matched healthy controls and ADPKD participants […]
- by Di Blasio, S., Middlekoop, A., Molist, F., Cord-Landwehr, S., Elrayah, A. A., Guardabassi, L., Good, L., Pelligand, L.Managing post-weaning diarrhoea (PWD) in piglets is difficult due to limits on antibiotics and zinc. Chitosan is emerging as a potential feed additive. We analysed a chito-oligosaccharide hydrochloride (COS-HCl), a low molecular weight (LMW) chitosan, and a medium molecular weight (MMW) chitosan, and assessed their effects on growth, faecal consistency, microbiota, and potential interference with enterotoxigenic Escherichia coli (ETEC). The three chitosans were characterised using {superscript 1}H-NMR, SEC-RI-MS, and SEC-RI-MALLS. COS-HCl had an Mw of 0.824 kDa; LMW and MMW […]
- by Sun, K., Liu, Y., Zhao, H.Bullous pemphigoid (BP) is an autoimmune blistering disease with a growing incidence, and environmental factors are receiving increasing attention. Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, is a significant environmental pollutant. However, the molecular mechanisms by which TBBPA contributes to BP pathogenesis remain unclear. This study integrated network toxicology, molecular docking, and molecular dynamics (MD) simulations to systematically investigate the molecular mechanisms of TBBPA-induced BP. Using network toxicology, we identified 797 potential targets of TBBPA and 446 BP-related […]
- by Webb, E. M., Cao, S., Pan, Y., Zhang, M.-Z., Harris, R., Boutaud, O., Bouchard, J. L., Jones, C. K., Lindsley, C. W., Hamm, H. E.Acute kidney injury (AKI) is a serious and common clinical syndrome that currently has no effective treatment. Emerging evidence links coagulation pathways to kidney injury, particularly through coagulation proteases. Protease-activated receptors (PARs) are a family of G protein coupled receptors (GPCRs) that are activated by proteolytic cleavage of their N termini, exposing a tethered ligand that initiates receptor signaling. PARs have been shown to play a major role in inflammation, vascular regulation, and tissue injury. PARs play key roles in […]
- by Mato, J. M., Wong, G. L., Gooijer, Y., Safaei, A.Background/ObjectivesThe quality and characteristics of approved medicines can vary substantially depending on manufacturing processes and standards within a given country. The aim of the study was to compare the available marketed brands of ademetionine tablets derived from various countries in order to identify potential differences between the different formulations. MethodsWe performed comprehensive analyses of the physical, chemical, and dissolution characteristics of different formulations of ademetionine tablets marketed in China, India, Russia, Ukraine, and Uzbekistan, using the originator formulation of Heptral(R) […]
- by Upadhyay, S., Roggia, M., Yuan, S., Cosconati, S., Gabr, M.Targeting protein-protein interactions (PPIs) with small molecules is historically challenging due to shallow, solvent-exposed interfaces that lack classical binding pockets. Furthermore, employing traditional structure-based virtual screening (SBVS) across ultra-large chemical spaces to find novel chemotypes imposes prohibitive computational bottlenecks. Here, we report the first prospective, real-world application of the PyRMD2Dock platform, an AI-enforced SBVS workflow that integrates machine learning and standard docking available within the PyRMD Studio suite. To target the structurally demanding immune receptor CD28, a chemically diverse subset […]
- by Rojo-Bartolome, I., Ibanez, J., Cancio, I., Ortiz-Zarragoitia, M., Bilbao, E.Transcriptomic analyses are widely used to elucidate the molecular mechanisms driving gametogenesis and reproduction in fish, yet their accuracy depends heavily on appropriate normalization of gene expression data. Conventional approaches that rely on single or multiple reference genes are problematic during teleost oogenesis, as profound structural and physiological remodeling of the ovary challenges the assumption that commonly used reference transcripts remain stable. In this study, we assessed by qPCR the transcriptional variability of four widely used reference genes (actb, ef-1, […]
- by Gollapudi, B. B., Bus, J. E., Cassidy, P., Weinberg, J. T., Bemis, J. C., Torous, D. K., Dertinger, S. D., Lu, K., Li, A. A.Ethylene oxide (EtO) is primarily used as an intermediate in the manufacture of chemicals, with a minor use as a sterilant for medical equipment and food products. It is a direct-acting alkylating agent that reacts with cellular macromolecules, including proteins and DNA. EtO has been shown to induce tumors in rodents and humans. DNA reactivity has been the postulated mode of action (MOA) for its carcinogenicity. The current study has investigated the dose response for EtO-induced genetic damage to inform […]
- by Zamora, A., Rucavado, A., Escalante, T., Gutierrez, J. M., Camacho, E.Skeletal muscle regeneration is often impaired after acute muscle damage induced by viperid snake venoms, such as that of Bothrops asper, a medically-relevant species in Latin America. It has been shown that traces of venom that remain in the damaged muscle affect myogenic cells in culture, raising the possibility of inhibition of these toxins during the regenerative process as a way to improve regeneration. Using a mouse model of myonecrosis and regeneration, we evaluated the effects of Varespladib (a phospholipase […]
- by Liu, C.-W., Peng, J., Feng, J., Zhao, H., Wang, X., Gollapudi, B. B., Li, A. A., Bus, J. S., Lu, K.Ethylene oxide (EtO) is a highly reactive industrial chemical and classified as a known human carcinogen with a putative mutagenic mode of action (MOA). Its genotoxic potential is primarily mediated through alkylation of DNA, resulting in the formation of the mutagenic adduct O6-(2-hydroxyethyl)-2-deoxyguanosine (O6-HE-dG). The N7-(2-hydroxyethyl)guanine (N7-HE-G) adduct is formed in greater abundance and is generally considered to be non-mutagenic. However, dose-response relationships of these DNA adducts, particularly at low inhalation exposure levels (i. e., below 3 ppm), remain unknown. […]
- by Tavakolpournegari, A., Kannan, U., Gregory, M., Dufresne, J., Costantino, S., Lefrancois, S., Cyr, D. G.Environmental degradation and accumulation of plastics results in micro- and nanoplastics (MNPLs) that are small enough to cross biological barriers, including the blood-brain barrier. Microglia, resident immune cells of brain, are critical regulators of neuroimmune homeostasis and represent a cellular target of nanoplastic exposure. In this study, we assessed the neurotoxic effects of two sizes of polystyrene nanoplastics (PS-NPs; 100 nm and 500 nm) using integrated in vivo and in vitro exposure and washout paradigms. In vivo exposure in mice […]
- by Okunska, P., Borys, M., Rypulak, E., Piwowarczyk, P., Szczukocka, M., Raszewski, G., Czuczwar, M., Wiczling, P.1.Pharmacokinetic studies in critically ill patients are often constrained by small sample sizes, limiting the strength and generalizability of conclusions drawn solely from observed data. Bayesian inference offers a powerful strategy to address this challenge by incorporating prior knowledge. In this study, we evaluated two model-based approaches for characterizing the population pharmacokinetics of ceftolozane and tazobactam in critically ill patients, comparing nonlinear mixed-effects modeling with Bayesian hierarchical analyses. The Bayesian methods incorporated literature-derived prior information. The data was collected from […]
- by Campbell, M. J., Patel, M., Jiang, C., Wen, X., Xiao, S., Aleksunes, L. M.BackgroundRising global temperatures and eutrophication are increasing the intensity and frequency of cyanobacterial harmful algal blooms that release toxins including microcystin-LR (MC-LR). MC-LR inhibits protein phosphatases in the human liver and brain, but its accumulation in the placenta is unclear. Placental transporter expression varies across pregnancy and is influenced by physiological cues, such as low oxygen concentrations which activate HIF1A, and trophoblast cell fusion forming syncytiotrophoblasts that engage CREB-driven transcription. This study examined whether MC-LR accumulates in placental cells, which […]
- by Rahman, M. S., Hannan, J., Tasnim, R., Bhuiyan, M. M. M., Basu, C., Sammo, S. H., Sarkar, B. C., Islam, S. T., khan, S.Asparagus racemosus commonly known as Shatamull, is a medicinal plant with pharmacological applications documented in both Indian and British Pharmacopoeias and various traditional medicinal practices. Previous studies have reported that A. racemosus reduces hyperglycemia by enhancing insulin secretion. The aim of the current study was to assess the antihyperglycemic actions and explore the underlying mechanisms of action of A. racemosus utilizing in vitro carbohydrate digestion, glucose diffusion, glucose uptake, 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and preliminary phytochemical screening. The inhibition of carbohydrate digestion […]
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