- by Wang, X., Sun, J., Ahmad, S., Yang, D., Li, F., Chan, U. H., Zeng, H., Simoben, C. V., Houliston, S., Dong, A., Bolotokova, A., Gibson, E., Kutera, M., Ghiabi, P., Kondratov, I., Matviyuk, T., Chuprina, A., Mavridi, D., Lenz, C., Joerger, A. C., Brown, B. D., Heath, R. B., Yue, W., Robbie, L. K., Beyett, T. S., Muller, S., Knapp, S., Harding, R. J., Schapira, M., Brown, P. J., Santhakumar, V., Ackloo, S., Arrowsmith, C. H., Edwards, A., Peng, H., Halabelian, L.We report an enantioselective protein affinity selection mass spectrometry screening approach (EAS-MS) that enables the detection of weak binders, informs about selectivity, and generates orthogonal confirmation of binding. After method development with control proteins, we screened 31 human proteins against a designed library of 8,210 chiral compounds. 16 binders to 12 targets, including many proteins predicted to be 'challenging to ligand', were discovered and confirmed in orthogonal assays. 7 binders to 6 targets bound in an enantioselective manner, with KDs […]
- by Toivio, L., Toivio, J., Linden, J., Lee, K., Lehto, M., Salmenkari, H., Korpela, R.High-fat, low-carbohydrate ketogenic diets have been found to alleviate experimental colitis in rodents. These diets lead to increased endogenous production and utilization of ketone bodies, such as {beta}-hydroxybutyrate (BHB), and supplementation with exogenous ketones has arisen as a potential alternative to ketogenic diets. This study aimed to investigate how continuous high-dose feeding with free acid BHB influences experimental colitis compared to a ketogenic diet with the hypothesis that BHB would also alleviate the inflammation. We fed nine-week-old C57BL/6J male mice […]
- by Reznik, S., Kashou, A., Ward, D., Yellon, S. M.The common excipient, N,N-dimethylacetamide (DMA), prevents imminent endotoxin-induced preterm birth in mice. The present study hypothesized that DMA forestalls preterm birth to term (defined as day 18.5 or later) by attenuating bacterial endotoxin lipopolysaccharide (LPS)-induced maternal systemic inflammatory responses and cervix remodeling. Accordingly, LPS (i.p.) on day 15 postbreeding stimulated preterm delivery within 24 h while mice treated with DMA 2 h preceding and 9 h following LPS administration remained pregnant, comparable to saline and DMA controls, to deliver viable […]
- by Mir, A., Acosta, T., Concheiro-Guisan, M., Yellon, S. M., Reznik, S. E.Vaginal administration and the uterine first pass effect allow for preferential delivery of drugs to the reproductive tract. Dimethylacetamide has previously been shown to delay preterm birth in a pregnant mouse model when given intraperitoneally but the effectiveness of a vaginal nanoformulation of dimethylacetamide has yet to be tested. The purpose of this study was to compare the two formulations of dimethylacetamide for efficacy in rescuing pups from preterm birth in an inflammation-induced mouse model, effects on the maternal fetal […]
- by Di Sano, C., D'Anna, C., Li Petri, G., Angellotti, G., Meneguzzo, F., Pagliaro, M., Ciriminna, R.Citrus IntegroPectin bioconjugates obtained through acoustic cavitation in water of different citrus fruit (lemon, red orange, and sweet orange) processing waste show substantial anticancer activity in vitro against human non- small cell lung cancer cells. Dissolved in aqueous phase at different concentrations, all IntegroPectin phytocomplexes tested affected long-term proliferation and cell migration of adenocarcinoma cells of line A549. Compared to sweet orange, IntegroPectin from lemon and red orange were more effective in reducing colony formation activity. Pointing to significant reduction […]
- by Ramos Docampo, E., Garcia-Fernandez, J., Marmol, I., Morin-Jimenez, I., Iglesias Baleato, M., de la Fuente Freire, M.Sphingomyelin Nanoemulsions (SNs) are promising drug delivery systems with potential for treating challenging tumors, including Non-Small Cell Lung Cancer (NSCLC), which has poor prognosis and a 5-year survival rate below 5%. Understanding the toxicity mechanisms and intracellular behavior of SNs is crucial for optimizing their therapeutic application. This study aims to investigate the interaction between SNs and A549 lung adenocarcinoma cells, focusing on their cytotoxic effects and mechanisms of cellular toxicity. SNs were synthesized and characterized for size, surface charge, […]
- by Guadarrama, E., Vanoye, C. G., DeCaen, P. G.Background and PurposePolycystins (PKD2, PKD2L1) are voltage-gated and Ca2+-modulated members of the transient receptor potential (TRP) family of ion channels. Loss of PKD2L1 expression results in seizure-susceptibility and autism-like features in mice, whereas variants in PKD2 cause autosomal dominant polycystic kidney disease. Despite decades of evidence clearly linking their dysfunction to human disease and demonstrating their physiological importance in the brain and kidneys, the polycystin pharmacophore remains undefined. Contributing to this knowledge gap is their resistance to drug screening campaigns, […]
- by Manchanda, Y., Jones, B., Carrat, G., Ramchunder, Z., Marchetti, P., Leclerc, I., Thennati, R., Burade, V., Natarajan, M., Shahi, P., Tomas, A., Rutter, G. A.The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss in type 2 diabetes (T2D) patients. Agonists which bind and stimulate multiple receptors have shown particular promise. However, off target effects, including nausea and diarrhoea, remain a complication of using these agents, and modified versions with optimized pharmacological profiles and/or biased signaling at the cognate receptors are increasingly sought. Here, we describe the synthesis and properties of […]
- by Hossain, M. A., Mayo, A. K., Ghoshal, A., Taft-Benz, S. A., Anderson, E. J., Morales, N. L., Pressey, K. D., Vargason, A. M., Brouwer, K. L. R., Moorman, N. J., Heise, M. T., Willson, T. M.RA-0002034 (1) is a potent covalent inhibitor targeting the alphavirus nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of 1 were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S-transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower clearance observed in human hepatocytes and preclinical species such as rats, dogs, and monkeys. Cross-species studies confirmed the dominance of GST-driven metabolism in mice, whereas oxidative pathways were more pronounced in dogs. Despite […]
- by Zhang, L., Mobbs, J. I., Bennetts, F. M., Venugopal, H., Nguyen, A. T. N., Christopoulos, A., van der Es, D., Heitman, L. H., May, L. T., Glukhova, A., Thal, D. M.Adenosine receptors (ARs: A1AR, A2AAR, A2BAR, and A3AR) are crucial therapeutic targets, yet developing selective, efficacious drugs remains challenging. Here, we present high-resolution cryo-electron microscopy (cryo-EM) structures of the human A3AR in three distinct functional states: bound to the endogenous agonist adenosine, the clinically relevant agonist Piclidenoson, and the covalent antagonist LUF7602. These structures, complemented by mutagenesis and pharmacological studies, reveal a unique A3AR activation mechanism involving an extensive hydrogen bond network from the extracellular surface down to the orthosteric […]
- by Adewuyi, H. A., Shekari, A., Adio, S. W., Oluwatoyin, A. H., Fagbohun, R. O., Owoeye, E. A., Korie, G. C., Nasiru, M. O., Olusegun, T. G.-G., Ishola, A. B., Gidado, M. O.BackgroundCadmium chloride is a toxic heavy metal that can cause oxidative stress, damage to organs, and disrupt hormonal balance. Brideliaferruginea is a plant with antioxidant and free radical-scavenging properties. The aim of this study was to investigate the protective effects of Brideliaferruginea extract against cadmium chloride-induced toxicity in rats. MethodsThis study used a randomized controlled design, with 36 rats divided into 6 groups. The rats were treated with cadmium chloride, Brideliaferruginea extract, or a combination of both. The study employed […]
- by Massey, N., Bhat, S. M., Shrestha, D., Malovic, E., Karriker, L. A., Choudhary, S., Robertson, A., Nguyen, H. M., Wulff, H., Kanthasamy, A., Charavaryamath, C.BackgroundAgricultural contaminants, including inhaled organic dust (OD) and gases, are known to cause inflammation in the lungs and the brain. We investigated the role of the potassium channel Kv1.3 in organic dust (OD)-induced neuroinflammation models. Kv1.3 channels play a multifaceted role in microglial immune modulation, cancer, neurodegenerative diseases, and constitute a potential therapeutic target. MethodsWe used in vivo (C57BL/6 mice), in vitro (microglial cell line, primary microglia), and ex vivo (brain slice culture) models of OD-induced neuroinflammation. A sterile OD […]
- by Woods, V., Umansky, T., Russell, S. M., McGovern, B. L., Rosales, R., Rodriguez, M. L., van Bakel, H., Sordillo, E. M., Simon, V., Garcia-Sastre, A., White, K. M., Smith, D. M., Haders, D.The death toll and financial stress posed by the recent COVID-19 pandemic have highlighted the pressing need to develop safe and effective, broad-spectrum inhibitors to treat viral infections. To accelerate the antiviral drug discovery process, we developed GALILEOTM, a computational platform that interfaces with a customizable bioinformatics pipeline with a geometric deep learning algorithm we named ChemPrintTM for in silico drug screening. Combining these algorithms with a large chemical repositioning library, we discovered MDL-001, which interacts with the Thumb pocket […]
- by Caroli, J., Andreassen, S. N., Lorente, J. S., Xiao, B., Pandy-Szekeres, G., Gloriam, D.G protein-coupled receptors (GPCRs) have been targeted across all therapeutic areas, mediate the actions of 516 (36% of all) approved drugs and are being targeted by 337 agents in clinical trials. So far, 121 GPCRs are targets of approved drugs and 30 additional receptors have entered clinical trials and may expand the drugged GPCRome in the coming years. Here, we describe an online resource of GPCR drugs, clinical trial agents, targets and disease indications. This resource offers unique reference data, […]
- by Huayta, J., Seay, S., Laster, J., Rivera, N. A., Joyce, A. S., Ferguson, P. L., Hsu-Kim, H., Meyer, J.Few of the many chemicals that regulatory agencies are charged with assessing for risk have been carefully tested for developmental neurotoxicity (DNT). To speed up testing efforts, as well as to reduce the use of vertebrate animals, great effort is being devoted to alternate laboratory models for testing DNT. A major mechanism of DNT is altered neuronal architecture resulting from chemical exposure during neurodevelopment. Caenorhabditis elegans is a nematode that has been extensively studied by neurobiologists and developmental biologists, and […]
- by Zylko, A. L., Rakoczy, R. J., Roberts, B. F., Wilson, M., Powell, A., Heitkamp, M., Fiest, D., Jones, J. A., McMurray, M. S.Psilocybin, a psychedelic compound in "magic" mushrooms, has promise as a novel treatment for psychiatric disorders, many of which are more prevalent in females and have onsets during adolescence. However, there is a lack of research about how factors such as sex and age affect responses to psilocybin, as well as potential safety concerns with developmental exposure. The primary objectives of this preclinical study were to determine if psilocybin-induced head twitch responses differ between adolescent and adult rats, and if […]
- by Pellegrino, M., Bindzus, M., Kottom, T., Ayyalasomayajula, S., Yi, J., Limper, A.Background and ObjectivePreviously, the novel small molecule ISFP10 has been shown to inhibit fungal phosphoglucomutase (PGM) activity in Aspergillus fumigatus and Pneumocystis spp. With 50-fold selectivity over the human PGM molecule due to the presence of a unique yet conserved cysteine residue present in a number pathogenic fungal PGMs, use of this compound may provide a novel broad-spectrum approach to treating fungal infections. Accordingly, we sought to determine the tolerability in test animals receiving this compound, as well as the […]
- by LI, Q., BAI, H., YU, X., LIU, Q., HU, R.Rabies is a preventable zoonotic disease caused by the rabies virus (RABV) with a high mortality rate. Most vaccines on the market or under development have issues such as a low single-dose neutralization titer, complex processes, and high costs. During the COVID-19 pandemic, the successful development of mRNA vaccines has opened up a new avenue for preventive vaccines. As a new technology, mRNA has higher scalability. In this study, we designed an mRNA encoding the RV-G protein, encapsulated by our […]
- by Ebenezer, I. S.Chronic intraperitoneal (ip) administration of the GABAB receptor agonist baclofen has been shown to reduce body weight in rats without significantly affecting daily food intake. The present study was undertaken to extend these observations to another rodent species. Male C57B/10 mice (n=27) that had free access to food and water were injected once daily for 15 days with either saline or baclofen (4 or 8 mg / kg; i.p). Body weight and food intake were measured 24h after each injection. […]
- by Thorpe, D. W., Mayo, B., Bresland, J., Stringer, A.Alimentary mucositis (AM) is a common side effect of antineoplastic treatment and a key reason for cessation of treatment, compromising the chance of remission. Gastrointestinal mucin secretion is associated with regulatory compounds nitric oxide and its respective synthases inducible, epithelial and neural nitric oxide synthase (iNOS, eNOS and nNOS, respectively), vasoactive intestinal polypeptide (VIP), and prostaglandin E2 (PGE2). Changes in secretion during mucositis have been demonstrated in numerous studies, however no secretory regulatory signals have been associated in mucositis induced […]
Mass spectrometry websites, social media, journal feeds, and other links and items of interest to the mass spectrometry community.
