- by Kottom, T., Limper, A.ABSTRACT Background: The newly identified small molecule ISFP10 has demonstrated the ability to inhibit fungal phosphoglucomutases (PGM), leading to decreased fungal growth and survival. Exhibiting 50 times greater selectivity for fungal PGM compared to the human homolog, ISFP10 shows promise as a broad-spectrum antifungal and a candidate for preliminary testing in rodent models of fungal infections, including Pneumocystis pneumonia (PCP). In preparation for targeted and relevant administration of the drug in fungal mouse models of infection, the current study describes […]
- by Aiken, S. G., Fiorito, D., Harper, M., Pikus, G., Underhill, J., Murray, J., Rawlinson, J., O'Donoghue, A. C., Gotti, C., Lummis, S., Minguez Vinas, T., Viscarra, F., Bermudez, I., Gallagher, T., Oliveira, A. S. F.Approved by the FDA in 2006, varenicline became the first nicotinic-based therapeutic for smoking cessation and has since been used by tens of millions of smokers worldwide. Varenicline works by targeting the 4{beta}2 nicotinic acetylcholine receptor (nAChR), the primary focus for nicotine addiction, where ligand recognition by the receptor triggers ion channel opening. While widely recognized that varenicline's development was rooted in the well-established pharmacology of cytisine, the two compounds display notably different profiles, not only at nAChRs, but also […]
- by Majumder, E. L.- W., Chatman, C. C.Atmospheric deposition, and agricultural runoff or erosion events have substantially contributed to groundwater pollution throughout the USA. This can become troublesome in states like Wisconsin where 68% of the population rely on groundwater for their drinking water source. As such, exposome research must account for the complexity and frequency of environmental exposures. This study aimed to elucidate chemical-biological interactions and adverse outcome pathways associated with an environmentally relevant mixture of agricultural chemicals detected in Wisconsin groundwater via in vitro and […]
- by Asamoah, S., Pravda, M., Snejdrova, E., Cepa, M., Jiri, M., Gruber-Traub, C., Velebny, V.Drug delivery to the central nervous system (CNS) is primarily hindered by the blood-brain barrier (BBB). To address this, mucoadhesive formulations have been designed to prolong residence time at the application site. In this study, we comprehensively characterized the physicochemical and mucoadhesive properties of hyaluronic acid tyramine (HATA) photocrosslinked hydrogels using rheological methods, nanoindentation, contact angle goniometry, and advanced confocal microscopy. A novel parameter, photon count per pixel, was introduced through confocal microscopy to assess hydrogel stability and mucoadhesion on […]
- by Tripathi, G., Bindal, V., Yadav, M., Sharma, N., Pandey, S., Mathew, B., Sharma, N., Yadav, S., Sharma, V., Sharma, S., Sarin, S. K., Maras, J. S.Introduction Withania somnifera (Ashwagandha) is a widely used medicinal plant with established roles in traditional systems of medicine. Known for diverse pharmacological effects, including neuroprotection, hepatoprotection, enhancement of male fertility, and anti-inflammatory activity. Despite its longstanding use, a deeper understanding of its phytochemical composition and bioactive mechanisms is required to bridge traditional knowledge with modern therapeutic applications. Methods A comprehensive metabolomics profiling of Withania somnifera was performed to identify and quantify its bioactive secondary metabolites. Focus was placed on major […]
- by Nicholson, S., Hewitt, K., Brauen, C., Henricks, A. M.Prenatal exposure to infection is a risk factor in the development of several neuropsychiatric disorders, including schizophrenia and depression, which often co-occur with alcohol misuse, exacerbating adverse outcomes. Despite these consequences, little is understood regarding the mechanisms by which early exposure to infection might increase the risk of alcohol misuse. We have previously demonstrated that maternal immune activation (MIA) combined with adolescent alcohol exposure (AA) increases home-cage drinking and disrupts neural circuit function in adulthood. The current project aims to […]
- by Novrial, D., Inayati, N. S., Gumilas, N. S. A., Kurniawan, D. W., Sumitro, S. B.Nanobubble technology exhibits outstanding stability and permeability and has been extensively developed in pharmaceuticals, dentistry, and medicine. The Hydrogen Nano Bubble (HNB) solution containing NO and magnesium is projected to have an even greater therapeutic effect than has ever been investigated. An experimental study using Sprague-Dawley rats was conducted to assess the intravenous injection's safety. Each rat received a single injection into the tail vein at a dose of 2 mL. On the other hand, aquades were injected into the […]
- by Omran, A., Fuezi, B., Amberg, A., Ecker, G. F.The Medical Dictionary for Regulatory Activities (MedDRA) is a standardized international medical terminology widely used in databases that collect adverse event data for drugs. MedDRA employs a hierarchical structure, allowing for analysis at different levels of granularity. However, as the volume of adverse event data continues to grow, and given MedDRAs complexity, it becomes increasingly challenging to analyze, and visualize the information effectively. To address this, PharmAverse was developed–an interactive dashboard designed to facilitate the analysis and visualization of adverse […]
- by Bedard, M. L., Seim, R. F., Brown, A. R., Cline, C. A., Gilley, K. R., Huffstickler, M., Nakkala, P. B., Rausser, S., Dasgupta, N., Strickland, J. C., Coleman, L. G., McElligott, Z. A.Xylazine, a veterinary sedative increasingly found in the unregulated drug supply, is associated with severe skin wounds in humans, particularly when co-used with fentanyl. Despite growing concern, the mechanisms underlying these wounds remain unclear. To investigate how xylazine and fentanyl affect wound healing, we administered subcutaneous injections of saline, xylazine (3.2 mg/kg), fentanyl (1.0 mg/kg), or their combination to female C57BL/6J mice for 28 days. After a standardized punch biopsy, wound closure was tracked for 14 days, with continued drug […]
- by Gonzalez-Prada, J. E., Haworth, A., Browne, J., Salvage, S. C., Secomandi, N., Rush, A., Ritoux, A., Dannawi, M., Lee, L., Mavridou, V., Dong, Y. Y., Smith, E. S. J., Jackson, A., Stevens, E., Miller, P. S.Background and PurposePeptide toxins isolated from animal venom are potent and selective modulators of ion channels, and promising therapeutic leads. Due to intricate disulphide bridge patterns, they are often challenging to produce in standard laboratory settings, which limits engineering approaches to manipulate their structure-function properties. Given the low cost, wide accessibility, and versatility of recombinant expression systems for protein production, we set out to establish a straightforward high-yield strategy across a broad panel of peptide toxins from snakes, spiders and […]
- by Agogo-Mawuli, P. S., Sadiya, I., Bosch, D. E., Emmitte, K. A., Colon-Perez, L., Kosloff, M., Siderovski, D. P.Regulator of G protein Signaling-14 (RGS14), an intracellular inactivator of G protein-coupled receptor (GPCR) signaling, has long been considered an undruggable protein due to its shallow and relatively featureless protein- protein interaction interface. Here, we describe the successful identification and validation of a tractable chemotype that selectively inhibits the GTPase-accelerating protein (GAP) activity of RGS14. Combining structure-guided virtual screening, ligand docking across multiple available receptor conformers, and enrichment validation, we progressed from an initial first-generation active compound, Z90276197, to over […]
- by Calvo-Barreiro, L., Nada, H., Upadhyay, S., Gabr, M.CD28 is a critical costimulatory receptor involved in T cell activation and immune regulation, making it a compelling target for immunomodulatory therapies. Despite its therapeutic relevance, small molecule CD28 inhibitors remain largely underexplored. To address this gap, we developed a high-throughput screening (HTS) workflow using surface plasmon resonance (SPR) to identify novel CD28-targeted small molecules. To our knowledge, this work represents the first SPR-based HTS platform applied to the discovery of small molecules targeting a stimulatory immune checkpoint receptor. A […]
- by Ye, J., Tan, J., Lin, Y., Guo, M., Duan, H., Zhang, F., Yang, X.Amidst the growing global burden of alcohol-associated liver disease (ALD) and the limited clinical interventions, this study innovatively developed a complex of Scutellariae Radix and corn-soy composite peptides (SR-CP). SR-CP exhibited significantly enhanced bioaccessible antioxidant capacity, demonstrating a 0.84-2.89-fold increase in DPPH, ABTS, {middle dot}OH, O2-{middle dot}, and FRAP value versus individual components post-gastrointestinal digestion. In ethanol-injured BRL-3A hepatocytes, SR-CP (60 g/mL) significantly ameliorated cellular viability by 38.28% (vs. ethanol model), normalized ALT/AST leakage by 19.92%/87.35%, restored SOD/GSH antioxidant reserves […]
- by Griffen, E. J., Fearon, D., McGovern, B. L., Koekemoer, L., Balcomb, B. H., Szommer, T., Fate, G., Robinson, R. P., Lefker, B. A., Duberstein, S., Lahav, N., Braillard, S., Vangeel, L., Laporte, M., Charvillon, F. B., MacLeod, A. K., Wells, A., Garner, P., Knight, R., Rees, P., Simon, A., Jochmans, D., Neyts, J., Read, K. D., Barr, H., Robinson, M., Lee, A. A., London, N., Chodera, J., von Delft, F., White, K. M., Perry, B., Sjo, P., von Delft, A. R.The 2020 SARS-CoV-2 coronavirus pandemic highlighted the urgent need for novel small molecule antiviral drugs. (S)-x38 DNDI-6510 is a non-covalent SARS-CoV-2 main protease inhibitor developed by the open science collaboration COVID Moonshot. Here, we report on the metabolic and toxicologic optimization of the lead series previously disclosed by the COVID Moonshot Initiative, leading up to the selection of (S)-x38 DNDI-6510 as the preclinical candidate. We describe the thorough profiling of the series, identifying key risks such as formation of genotoxic […]
- by Brauer-Nikonow, A., Voogdt, C. G. P., Ribeiro, N. V., Zimmermann, M.The epithelium of the human gastrointestinal tract is key for controlling the absorption of small molecules and for forming a tight barrier between the gut microbiota and the host, thereby maintaining metabolic homeostasis. Both the microbiota and the barrier function of the intestinal epithelium have a role in pharmacokinetic variability of medical drugs. In this study, we developed a high-throughput workflow to assess the absorption of bacterially produced (drug) metabolites by intestinal epithelial cells through the combination of anaerobic bacterial […]
- by Lengyel, M., Arkosy, P., Uray, I. P.In the healthy mammary gland serotonin (5-HT) has a key role in shaping tissue morphology and regulating lactation and involution. Serotonin re-uptake inhibitors (SSRIs) alter the distribution of 5-HT across the cell membrane, but how increased extracellular 5-HT may impact breast cell homeostasis is unclear. We demonstrate that paroxetine reduces 5-HT levels in immortalized primary breast epithelial (HME-hTert) cells, mitigates free oxygen radical formation and decreases cell migration and proliferation. Accordingly, pathways related to cell cycle and DNA damage repair […]
- by Hetzler, B. E., Donthamsetti, P. C., Wolesensky, R. M., Stanley, C., Isacoff, E., Trauner, D.Dopamine D1 receptor (D1R) plays key roles in health and disease. D1R is broadly expressed throughout the brain and body and is dynamically activated in response to endogenous dopamine, making it difficult to target this receptor with sufficient precision. We previously developed a robust light-activatable, tetherable agonist for D1R, wherein a temporally precise photo-switch (the P compound) binds to a genetically-encoded membrane anchoring protein (the M protein) in specific brain locations and cell types. Here we extended our approach by […]
- by Shah, I., Gallegos, D., Robinette, B., Chambers, B. A., Eastburn, D., Camiolo, S., White, K., Martin, N., Montis, G., McComb, J., Seligmann, B., Chorley, B. N.We applied the TempO-LINC(R) platform to generate single-cell transcriptomic (SCTr) profiles of [~]40,000 HepaRG cells exposed to etoposide, brefeldin A, cycloheximide, rotenone, tBHQ, troglitazone, and tunicamycin at three concentrations for 24 hours. SCTr enabled a detailed analysis of adaptive stress response pathways (SRPs), including the unfolded protein response (UPR), oxidative stress response (OSR), heat shock response (HSR), and DNA damage response (DDR). Troglitazone upregulated lipid metabolism genes (PLIN2, ACOX1) along with HSR and UPR activation, with co-expression of DNAJA1, HSP90AA1, […]
- by Kalailingam, P., Ngan, S. C., Gallart-Palau, X., Serra, A., Datta, A., Ch'ng, T. H., Tsiani, E. L., Klentrou, P., Kalaria, R. N., McCarthy, N. E., De Kleijn, D., Sze, S. K.BackgroundDegenerative protein modifications (DPMs) accumulate with aging and can alter biomolecule structure and function, including via spontaneous conversion of Asn-Gly-Arg (NGR) to isoAsp-Gly-Arg (isoDGR) motifs that can bind integrins and drive chronic inflammation. Since isoDGR-modified extracellular matrix proteins are enriched in atherosclerosis and have been associated with rupture-prone plaque characteristics, we hypothesized that antibody neutralisation can inhibit key pathological features including atherosclerotic vascular plaque formation and metabolic dysfunction. MethodsWe first examined Pcmt1-/- mice which rapidly accumulate isoDGR due to lack […]
- by Rountree, C., Rodriguez, T., Byrne, E., Schmidt, E., Schwarzbach, E., Dillon, S., McCrimmon, A., Terral, M., Metea, M., Moore, M. J., Curley, J. L.Reliable human-relevant models of peripheral nerve function remain a critical unmet need in preclinical drug development, particularly for predicting neurotoxicity and bridging the gap to clinical translation. Here, we introduce a next generation Nerve-on-a-Chip, PNS-3D organoids, as a novel human-cell-based 3D peripheral nerve microphysiological system (MPS) that recapitulates key functional and structural features of native nerves, including long-distance axonal outgrowth, physiological myelination, and clinically translational population level electrophysiology. The platform integrates iPSC-derived human sensory neurons and primary human Schwann cells […]
Mass spectrometry websites, social media, journal feeds, and other links and items of interest to the mass spectrometry community.
