- by Kotova, P. D., Dymova, E. A., Lyamin, O. O., Rogachevskaja, O. A., Voronova, E. A., Kolesnikov, S. S.The inhibitory analysis of intracellular signaling pathways is widely employed to gain insight into molecular mechanisms underlying diverse physiological processes. Unfortunately, the essential drawback of this basically effective methodology is that many, if not all, inhibitors, antagonists, modulators, and blockers can affect cellular functions not only acting through specified cellular targets, but also causing off-target effects. In particular, the class I phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and its PI3K-inactive structural analog LY303511 have been shown to affect agonist-induced Ca2+ signaling in […]
- by Costa, C. N., Ciapina, L. P., Bahia, A. C., Neto, V. B. d. S., da Silva, F. A. B., Lopes, F. J. P.Cisplatin, the first metal-based chemotherapeutic drug, remains widely used in treating various solid cancers despite its side effects and drug resistance. To mitigate these issues, researchers have explored combining Cisplatin with different substances. Various carriers or associated nanoparticles have been studied with Cisplatin, primarily using in vitro models. In this context, Drosophila melanogaster serves as a valuable alternative model for evaluating the toxicity of numerous substances and studying diseases like cancer, Alzheimers, and alcoholism. This work investigates the in vivo […]
- by Tsuchiya, H., Hanaki, T., Obora, M., Yoshida, J., Fujiwara, Y., Nanba, D.The tumor microenvironment (TME) provides a niche for immune evasion and immunotherapy resistance, in part, by recruiting pro-tumor M2-like macrophages. In the present study, using heterospheroids consisting of cancer cells and macrophages, we identified TAM activators, which are compounds that reprogram M2-like tumor-associated macrophages (TAMs) toward the antitumor M1-like phenotype. THP-1- or human peripheral monocyte-derived macrophages were co-cultured with liver cancer cells in an ultra-low attachment dish to generate heterospheroids. Cell surface marker expression and macrophage infiltration into the heterospheroids […]
- by Huang, Y., Chang, R. C., Nguyen, K. U., To, K. T., Deeprompt, K. G., Gibbs, M., Shioda, T., Blumberg, B.Obesity has become a global health challenge, and increasing evidence suggests that environmental obesogens contribute to its prevalence. Tributyltin (TBT) is a model obesogen known to activate PPAR{gamma} and RXR and to promote transgenerational obesity in mice, but the mechanisms linking TBT exposure to impaired energy balance remain poorly defined. Brown adipose tissue (BAT) is a central regulator of energy expenditure (EE) and basal metabolic rate (BMR) through both UCP1-dependent and UCP1-independent pathways. Here, we tested whether ancestral TBT exposure […]
- by Aguilar Ayala, D. A., Rabodoarivelo, M. S., Eveque-Mourroux, M. R., Leding, A. A., Sonnekalb, L., Pico Marco, A., Willand, N., Serbina, N., Simonsson, U. S., Lucia, A., Ramon-Garcia, S., ERA4TB consortiumThe first-in-class diarylquinoline (DARQ) bedaquiline (BDQ) is in the medicines list for drug-resistant tuberculosis. TBAJ-587 is a next-generation DARQ with improved anti-Mycobacterium tuberculosis (Mtb) activity and reduced cardiac repolarization abnormalities. Methods. The in-vitro efficacy of TBAJ-587 and its main metabolites (M2, M3 and M12) was analyzed under standard (ST) growth conditions, with cholesterol (CHO), or fatty acids (FA) as alternative carbon sources. Minimal inhibitory concentration (MIC) assays and time-kill assays (TKA) linked to drug measurements in bacterial samples were performed […]
- by Onaolapo, O., Aworinde, O., Olufemi-Aworinde, K. J., Onaolapo, A. Y.Infertility, defined as the inability to achieve pregnancy after 12 months of unprotected intercourse, is a major reproductive health concern. In females, hyperandrogenism often contributes to polycystic ovarian syndrome (PCOS), a leading cause of infertility. Although clomiphene and letrozole are widely used as ovulation inducers, their individual efficacy is limited, and the potential benefit of combined therapy remains unclear. This study investigated the effects of clomiphene-letrozole co-administration on gonadotrophic hormones, inflammatory cytokines, antioxidant status, and ovarian histomorphology in a rat […]
- by Shelley, J., Chai, Q., Wu, L., Vafaei, S., Shelley, M. Y., Feyfant, E., Feng, J., Woldeyes, M., Babin, V., Jou, J.Computational prediction of the viscosity of therapeutic monoclonal antibodies (mAbs) at high concentration is highly desirable in the early discovery and development phases where the material needed for experimental determination is typically limited. Here, we present a unique coarse-grained (CG) simulation method that enables residue-level simulation of full-length antibodies with an elastic network, under simulated shearing force, to de novo predict viscosities of solutions of two distinct mAbs (an IgG1 and an IgG4), in the absence and presence of 6 […]
- by Porta, E. O. J., Koutsogiannis, Z., Kalesh, K., Denny, P. W., Steel, P. G.This chapter details an activity-based chemoproteomic methodology, INTERACT (Interactome Network Targeting via Enzyme Reactivity and Activity-based Chemoproteomic Tools), for the functional interrogation of host-pathogen interactions (interactome) in a physiologically relevant context. The exemplar protocol utilises a small, cell-permeable fluorophosphonate probe to covalently label active serine hydrolases simultaneously within Leishmania mexicana parasites and their murine macrophage host cells during active infection. Subsequent biorthogonal click chemistry, affinity enrichment, and quantitative mass spectrometry using Tandem Mass Tags (TMT) enable the identification and relative […]
- by Guenther, K. G., Crystal, J. D., Hohmann, A. G.Cannabinoid CB2 agonists reduce stimulus-evoked behavioral hypersensitivities in preclinical pain models, but their ability to modulate spontaneous pain remains unexplored. Spontaneous pain has been assessed in rodents using the conditioned place preference (CPP) approach, given that the relief of pain is described as rewarding and results in negative reinforcement (i.e. removal of an aversive pain state). LY2828360 is a CB2 agonist that failed in a clinical trial for osteoarthritis pain. We compared impact of LY2828360 on evoked and spontaneous pain […]
- by Varley, S., Clark, T., Chubb, N., Lamassiaude, N., Charvet, C., Neveu, C., Forrester, S.Nematode cys-loop GABA receptors play important roles in movement and locomotion. GABA receptors encoded by unc-49 appear to be widespread in nematode genomes including parasitic nematodes but are poorly characterized in filarial parasites. Dirofilaria immitis is a filarial parasite responsible for heartworm disease in dogs. Macrocyclic lactones are widely used to prevent heartworm infection. However, like many anthelmintics, resistance has emerged and new solutions are needed including the discovery of new anthelmintic drug targets. In this study, we report the […]
- by Youngs, R.Drug discovery productivity–measured as clinically viable new molecules per research has declined for decades, a trend known as Erooms Law. This paradox persists despite advances in screening, computing, and artificial intelligence. Here we show that it stems from two forces: the finite diversity of natures biosynthetic rules, leading to saturation of novel natural scaffolds, and the dilution of viable candidates in expanding synthetic chemical spaces, where success rates fall without improved specificity. We propose an optimized hybrid strategy that allocates […]
- by Phandthong, R., Rolon, E., Ramirez, B., Kudsi, M., Choi, A., Tahmasbi, A., Martinez, T., Talbot, P.Electronic cigarette (EC) aerosols are increasingly recognized for their disruptive effects on airway physiology, yet the temporal progression of epithelial remodeling remains poorly characterized. While squamous metaplasia, mucin hypersecretion, and ciliary dysfunction are hallmark features of smoking-related airway disease, analogous data for EC exposure are limited. To address this gap, we employed a 3D human tracheobronchial epithelial tissue (hTET) model derived from airway basal stem cells and exposed it daily to NJOY ACE "Classic Tobacco" aerosols (1 or 5 puffs) […]
- by van de Beek, H., Välitalo, P. A. J., van Hasselt, C. J. G., Zwep, L. B.Pharmacometric modelling is traditionally performed using individual level data. Recently a new method was developed to fit pharmacometric models to summary level – or aggregate – data. This methodology allows for jointly modelling different data sources, once transformed into aggregate data. As such, the method can be applied to a combination of individual data, pharmacometric models, and aggregate data. In this study we aimed to (1) implement this methodological framework into an accessible R package (admr) and (2) develop a […]
- by Threadgill, D. W., Ming-Whitfield, B., Cuomo, D.Lead (Pb), chromium (Cr), and cadmium (Cd) are heavy metals that contaminate sites throughout North America. Historically, toxicological effects of Pb, Cr, or Cd compounds have been investigated in a hybrid mouse strain, B6C3F1. However, humans have more genetic diversity and population variability in response to toxicants than is represented in this homogeneous mouse model, which leaves genetic effects on dose response uncertain. Use of the Collaborative Cross (CC) addresses the problem of limited genetic diversity inherent in models like […]
- by imazu, t., Akashi, T., Hiraizumi, M., Inui, Y., Sasaki, W., Takahashi, T., Todoroki, H., Kumanomidou, T., Yamada, K., Fujikawa, N., Hisano, H., Asada, H., Kusakizako, T., Nishizawa, T., Iwata, S., Nureki, O., Miyaguchi, I.B0AT1 is a neutral amino acid transporter responsible for the (re)absorption in the intestine and kidney. Here, we developed small-molecule inhibitors of B0AT1 as a therapeutic strategy to a transient pocket, located [~]17 [A] away from the substrate-binding site and unique to the outward-open conformation, and stabilize an outward-occluded conformation that prevents the conformational transitions required for transport. Guided by structural insights, we optimized an initial inhibitor (Cinromide) to improve potency and cross-species activity, yielding compound 3, which inhibits both […]
- by Geci, R., Sayin, A. Z., Schaller, S., Kuepfer, L.Drug-induced liver injury (DILI) is a major cause of drug attrition and poses a significant threat to patient safety. However, current preclinical prediction methods, including heuristic screening rules, in vitro assays, machine learning models and animal testing, have serious limitations. Here, we demonstrate that combining in vitro toxicity data (cytotoxicity, mitochondrial toxicity, bile salt export pump (BSEP) inhibition) with pharmacokinetic information enables high DILI predictivity. In a retrospective analysis of 241 drugs, we show that the ratio of their in […]
- by Dhillon, I. U. S., Marchi, R. C., Ghadim, E. E., Huband, S., Liu, J., Sadler, P. J., Collingwood, J. F., Bakker, S. E., Brooks, J.Iron-rich nanoparticulate matter air pollution exposure is implicated in the pathophysiology of Alzheimers disease. The use of colorimetric cell viability assays to ascertain the potential cytotoxicity of iron oxide nanoparticles have highlighted conflicting results in various in vitro models, because of spectrophotometric interference. Attempts to resolve this confounding factor to reveal accurate measurements have been insufficient. To address this interference issue, we tested three control methods (readout correction, plate transfer, and above-plate reading) on in vitro cytotoxicity measurements via Neutral […]
- by Alijagic, A., Chaker, J., Barbosa, J. M. G., Duberg, D., Castro-Alves, V., Dickens, A. M., Oresic, M., Hyotylainen, T.Perfluorohexyloctane (F6H8) is a semifluorinated alkane recently approved for ophthalmic treatment of dry eye disease. Although considered locally safe for topical use, its structural similarity to persistent per- and polyfluoroalkyl substances (PFAS) raises concerns about systemic accumulation and long-term toxicity. To investigate potential hepatic effects, we examined the metabolic impact of F6H8 exposure in human HepaRG hepatocytes across a broad concentration range representing short- and long-term exposure scenarios. Untargeted metabolic profiling by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-OTOFMS) was […]
- by Madgaonkar, S. R., Chivukula, N., Garisetti, V., Marigoudar, S. R., Sharma, K. V., Samal, A.Adverse outcome pathways (AOPs) describe mechanisms of toxicity by connecting molecular events with outcomes at higher levels of biological organization. Computational AOPs (cAOPs), constructed using existing toxicological data, can accelerate the early stages of AOP development, which is often a time-consuming and resource-intensive process. In this study, an integrative network-based framework was developed to construct cAOPs, with a particular focus on elucidating the toxicity of organic mercury in fish. First, 124 organic mercury compounds, corresponding fish-specific toxicity endpoints, and proteins […]
- by Hughes, E. A., Davenport, L. L., Woodward, A., Patel, S., Lee, J., Zdyrski, C., Douglass, E. F., Pawlak, A., Allenspach Jorn, K., Mochel, J. P.In 2022, the average cost for a single drugs development increased by 15%, reaching $2.3 billion. In drug development, oncology has the highest attrition rate with 95% of new drugs failing Phase 2 clinical trials alone. Consequently, innovative approaches are needed to assess clinical utility prior to proceeding with human trials. Current drug development follows the theory that "Best Potency = Best Drug" which is a concentration-centric paradigm focused on optimizing drug-target interaction (Kd) to improve the concentration of drug […]
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