- by Mobbs, J. I., Nguyen, M. D., Deo, O., Bartuzi, D., Venugopal, H., Alvi, S., Pham, V., Barnes, N., Christopoulos, A., Poole, D. P., Carbone, S. E., Jorg, M., Capuano, B., Carlsson, J., Gondin, A. B., Scammells, P. J., Valant, C., Thal, D. M.Opioid analgesics remain essential for pain management but are associated with significant adverse effects, including respiratory depression, tolerance, and dependence. The {delta}-opioid receptor ({delta}OR) represents a promising therapeutic target for developing safer opioid analgesics with reduced adverse effects compared to conventional -opioid receptor-targeting drugs. Positive allosteric modulators (PAMs) offer advantages over direct agonists by enhancing endogenous opioid signaling while preserving natural spatiotemporal activation patterns, potentially avoiding tolerance and dependence issues. Here, we present high-resolution cryo-EM structures of {delta}OR complexed with […]
- by Shukla, H., Nasra, S., Patel, M., Bhatia, D. D., Kumar, A.Chronic inflammation, characterized by the infiltration of macrophages and the heightened release of pro-inflammatory cytokines, is the underlying cause of the pathogenesis of many critical diseases. Therapeutic interventions for controlling inflammation via gene knockdown of inflammatory mediators have emerged as a promising approach for regulating uncontrolled inflammation. This study explores the potential of siIL-1{beta}-anti-CD44-Liposomes (SIL) as a potent anti-inflammatory therapy against pro-inflammatory RAW264.7 macrophages via gene specific knockdown of IL-1{beta} mRNA through RNAi, and the subsequent down-regulation of the pro-inflammatory […]
- by Ramil, M. D., Heralde, F. M., Sasaki, K., Kobayashi, K.This study investigated the acute oral toxicity, in vitro angiotensin-converting enzyme (ACE) inhibitory activity, and metabolite profile of the aqueous fraction of the methanol leaf extract of Psychotria luzoniensis (PLAF), a plant endemic to the Philippines. ACE inhibition was evaluated in the crude extract, fractions, and sub-fractions through IC_50 determination. The most bioactive fraction was subjected to acute oral toxicity testing in mice at a limit dose of 2000 mg/kg body weight, and metabolite profiling was performed using UHPLC-QTOF-MS/MS. PLAF […]
- by PEZET, S., Hua, J., Marais, T., Delamare, M., Elouej, S., Lemos, J. P., Castiglione, A., Astord, S., Cohen Tannoudji, M., Peche, G. A., Rigamonti, M., Daniele, N., Genries-Ferrand, S., Buscara, L., Ratti, A., Bohl, D., Smeriglio, P., Biferi, M. G.Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neurons loss (MN). In 15-20% of familial ALS cases, mutations in the superoxide dismutase 1 (SOD1) gene are the underlying cause. Targeting human SOD1 (hSOD1) toxicity has emerged as a promising approach to treat SOD1-ALS. We previously demonstrated the efficacy of an exon-skipping strategy using a self-complementary AAVrh10-U7-hSOD1 vector in SOD1G93A mice achieving significant hSOD1 silencing. In this study, we optimized the therapeutic protocol by conducting a dose-finding […]
- by Sutrisna, E., Ariesto, M. R., Sulistyo, H., Purnawan, I.Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, contribute significantly to drug-induced gastrointestinal complications globally, primarily through prostaglandin inhibition and oxidative stress mechanisms. The search for safer, plant-based alternatives has intensified, particularly in resource-limited settings. This study aimed to evaluate the gastroprotective potential of Aleurites moluccanus (candlenut) oil in a rat model of aspirin-induced gastric injury. Twenty-five male Wistar rats were randomly assigned to five groups: a healthy control, a negative control, and three treatment groups receiving A. moluccanus oil at […]
- by Batres, J., Hunter, B., Shim, H.Bacteriophages offer advantages over small-molecule antibiotics, including host specificity and general compatibility with the human phagenome. However, their evolvability as replicating biological entities introduces therapeutic unpredictability and risks of phage-bacteria co-evolution. Here, we retain the targeting benefits of phages while avoiding genetic replication by engineering genetic-information-free, protein-only phages (POPs). These genome-free particles self-assemble in a cell-free protein synthesis system from modular, de novo gene fragments encoding only structural and antimicrobial proteins. Using Enterobacteria phage T7 and its susceptible bacterial host […]
- by Dolinska, M., Wang, Y., Coussens, N., Kalaskar, V., Eraslan, Z., Grondin, S., Bonica, J., Toay, S., Hall, M., Shen, M., Boxer, M., Chen, Q., Gross, S., Attarwala, N., Jittayasothorn, Y., Alur, R., Shukla, D., Kee, R., Deyoung, C., Sha, C., Adams, D., Loftus, S. K., Cogliati, T., Sergeev, Y. V., Zippin, J. H., Brooks, B.Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a unique human TYR construct, high-throughput screening, and computational analysis techniques, we identified ampyrone as a TYR activator. Ampyrone increased the in vitro catalytic activity of the intramelanosomal domain of […]
- by Brouillette, R. L., Lussier, F., Breault, E., Meneboo, N., Chartier, M., Midavaine, E., Cote, J., Blais, V., Mona, C. E., Longpre, J.-M., Grandbois, M., Audet, M., Besserer-Offroy, E., Sarret, P.Pepducins are synthetic membrane-tethered lipopeptides designed to allosterically modulate G protein-coupled receptor (GPCR) signaling. Here, we characterize a series of pepducins targeting the neurotensin receptor type 1 (NTS1), revealing multifaceted modulation of this receptor class. Using BRET-based biosensors, we show that PP-001, a pepducin derived from NTS1s first intracellular loop, preferentially activates G protein over {beta}-arrestin signaling while inhibiting NT binding, NT-induced {beta}-arrestin recruitment, and NTS1 receptor internalization, thereby acting as biased allosteric agonist and negative allosteric modulator. PP-001 also […]
- by Ecker, A., Szabo, G., Szalma, J., Ficho, E., Reguly, I., Csikasz-Nagy, A.Artificial intelligence plays an ever-greater role in preclinical drug development, ranging from target identification and molecule design to ADME-Tox prediction; however, predicting side effects before performing clinical trials is still lagging behind. The best performing side effect predictors in the literature use either ATC codes, which are expert-derived features not even available at early stages, or graph neural networks based on chemical similarity, which – although use readily available features – are "black boxes" that do not deliver actionable insights. […]
- by Campo, P., Qiao, R., Doyle, M. R., Munro, D., Johnson, B. J., Palmer, A. A., Kallupi, M., de Guglielmo, G.Although FDA-approved medications for alcohol use disorder (AUD) are available, their efficacy varies across patients, highlighting the need for novel therapeutics that address inter-individual differences in disease etiology and treatment response. Genetic models, particularly heterogeneous stock (HS) rats, recapitulate human-like genetic diversity and behavioral heterogeneity, enabling the dissection of individual differences in vulnerability to AUD and pharmacotherapeutic sensitivity. P2X4 receptors, which are encoded by the gene P2rx4, are ATP-gated ion channels inhibited by ethanol and abundantly expressed in neurons found […]
- by Zhang, H., Konovalov, K., Parpounas, A. K., Provasi, D., Yang, S., Abraham, A., Warren, A. L., Zilberg, G., Wang, S., Filizola, M., Wacker, D.Positive allosteric modulators (PAMs) of the opioid receptor (MOR) offer a promising path toward safer opioid therapeutics, yet their mechanisms of action remain poorly understood. Here, we uncover the structural and mechanistic basis of BMS-986187, a chemically distinct MOR PAM with in vivo efficacy, using an integrated approach combining cryogenic electron microscopy (cryo-EM), molecular dynamics (MD) simulations, signaling assays, and site-directed mutagenesis. We identify a previously uncharacterized allosteric site for BMS-986187, a lipid-facing pocket formed by MOR transmembrane helices 2, […]
- by Brewer, M., Kumar, A. H.Canine feeding behaviour is strongly influenced by taste perception, yet the molecular determinants of palatability, particularly umami taste is unclear. Dogs typically consume food rapidly with minimal mastication, relying on a limited number of taste buds to detect sour, bitter, salty, sweet, and umami flavours. Amino acids are known to play a central role in canine taste, especially in diets rich in animal proteins. In this study, we aimed to identify the specific amino acids that optimally stimulate umami perception […]
- by Jaishankar, P., Correy, G. J., Matsui, Y., Togo, T., Rachman, M. M., Stevens, M. G. V., Hantz, E. R., Zheng, J., Diolaiti, M. E., Montano, M., Taha, T. Y., Rosecrans, J., Pampel, J., Krogan, N. J., Shoichet, B. K., Ashworth, A., Ott, M., Fraser, J. S., Renslo, A. R.The COVID-19 pandemic made plain the need for effective antivirals acting on novel antiviral targets, among which viral macrodomains have attracted considerable attention. We recently described AVI-4206 (1), a potent and selective inhibitor of the SARS-CoV-2 ADP-ribosylhydrolase Mac1 based on a 9H-pyrimido[4,5-b]indole core, the first Mac1 inhibitor to demonstrate antiviral efficacy in mouse models of SARS-CoV-2 infection, but requiring IP administration and frequent dosing. Herein we describe an extensive, structurally enabled medicinal chemistry effort to identify orally bioavailable Mac1 inhibitors […]
- by Reynolds, A. J., Mickel, J. A., Nault, R., Qiu, T.Per- and polyfluoroalkyl substances (PFAS) are a class of emerging contaminants that are widely distributed and persistent in the environment, accumulated in biological organisms and associated with adverse health outcomes. Evidence has shown a wide existence of branched PFAS isomers from source to applications. Notably, linear and branched isomeric PFAS structures are associated with differential toxicity outcomes and health effects. Herein, we investigated distribution of perfluorooctane sulfonate (PFOS) isomers in mouse liver tissue after exposure using matrix-assisted laser desorption/ionization-trapped ion […]
- by Tarnoki-Zach, J., Boldizsar, I., Kovacs, G. M., Bosze, S., Czirok, A.The epithelial permeability of petasol, a sesquiterpene derivative with reported antiviral properties, remains largely unexplored despite its potential as a therapeutic candidate. Here, we systematically characterize the transport of petasol across epithelial barriers using a combination of in vitro transwell models, automated millifluidic sampling, mathematical modeling, optical- and HPLC-mass spectroscopy. Vero E6 and Caco-2 cell layers were employed as epithelial barrier models, with transepithelial electrical resistance (TEER) measurements confirming the formation of functionally intact epithelial layers. Mathematical modeling of passive […]
- by van Tellingen, O., Tolboom, Z. J., Leter, Y. M., Tsouri, E., Burylo, A., Van Heijningen, C., Schagen, S., de Gooijer, M. C., Kuil, L. E.BackgroundMicroglial reactivity, a hallmark of many neurodegenerative diseases, is thought to contribute significantly to disease pathology. In experimental models, colony stimulating factor 1 receptor (CSF1R) inhibitors transiently deplete microglia to resolve inflammation, leading to improved neuropathology. In oncology, CSF1R inhibitors modulate tumor-associated macrophages (TAMs) toward a tumor-suppressive phenotype by silencing CSF1-CSF1R signaling. As for any therapeutic, target engagement depends on effective drug delivery. In the brain a major hurdle is the limited drug delivery caused by the presence of the […]
- by Amadi, J. A., Alloy-Amadi, O. C., Chukwu, C. H., Amadi, P.BackgroundEndothelial dysfunction, dyslipidemia, and myocardial injury are major contributors to cardiovascular disease. Avocado (Persea americana), rich in monounsaturated fatty acids and phytochemicals, has shown lipid-lowering and anti-inflammatory properties, but its integrated effects on vascular injury remain unclear. MethodsMale rats were randomized into six groups (n = 4 per group): control, avocado, L-NAME, L-NAME+drugs (metoprolol+losartan), L-NAME+avocado, and L-NAME+drugs+avocado. Morphometric indices, lipid profiles, cardiac injury enzymes, and vascular biomarkers were measured after treatment. One-way ANOVA with Tukey test assessed group differences, while […]
- by Fosu, K., Ansah, E. O., Francis, O., Annor, D., Mati, D. T., Ehiobu, J. M., Mustapha, H., Laryea, M. N. A. A., Aikins, M., Ninson, E., Apeku, E. A., Halm, E., Adam, Y., Barnie, P. A., Kyei, F.Alcoholic liver disease (ALD) remains a major global health burden with limited therapeutic options. In this study, we investigated the hepatoprotective effects of Vernonia amygdalina (VA) leaf extract against ethanol-induced liver injury using integrated in vivo and in silico approaches. Wistar rats were exposed to ethanol to induce liver damage, followed by treatment with VA extract (100-300 mg/kg) or silymarin (50 mg/kg). Liver function indices were evaluated through biochemical analysis. Network pharmacology analysis was performed to identify active compounds and […]
- by Ruiz-Ederra, J., Lara-Lopez, A., Rodriguez-Hidalgo, M., Sarasola-Gastesi, M., Gonzalez-Imaz, K., Zayas, J., Sagartzazu-Aizpurua, M., Miranda, J. I., Espinosa, A., Lopez de Munain, A., Aizpurua, J. M., Gil-Bea, F. J., Vallejo-Illarramendi, A.MP-004 is a novel small molecule under development as a non-invasive therapeutic for inherited retinal dystrophies (IRDs), including retinitis pigmentosa. Here, we evaluated its ocular concentration and safety profile following topical administration in three animal species –mouse, rabbit, and pig–. MP-004 formulation with 0.3% hyaluronic acid significantly enhanced retinal concentration in mice compared to non-formulated compound (6.67 vs 1.27 {micro}g/g at 4 h). MP-004 reached therapeutically relevant retinal concentrations in all species tested, with minimal systemic exposure: in mice, levels […]
- by Jenkins, B. W., Pang, C., Kuang, R. Y., Weerts, E. M., Moore, C. F.Opioid use disorder (OUD) remains a public health crisis in the United States. A key factor in continued use, relapse risk, and overdose is the severe withdrawal syndrome that accompanies abstinence. Observational studies suggest cannabis may improve outcomes for patients with OUD. Cannabidiol (CBD), a non-intoxicating compound found in cannabis, is being investigated as a potential treatment for OUD. This study investigated whether CBD alleviated withdrawal symptoms in a rat model of opioid dependence. Sprague Dawley rats (N = 100, […]
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