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  • A novel antioxidant N-acetylcysteine Amide Alleviates Cyclophosphamide-induced Endothelial Damage
    by He, R., Zheng, W., Slof, T., Wardell, E., Mansson-Broberg, A., Norgren, S., Zhao, Y., Hassan, M.
    The alkylating agent cyclophosphamide (Cy) is one of the important corner stones in cancer treatment. Cy is used also as a part of conditioning regimens prior to hematopoietic cell transplantation and as a prophylactic treatment post transplantation in graft-versus-host disease. Existing evidence showed that high doses of Cy are associated with a number of side effects, including damage on arterial endothelium, which might contribute to late cardiovascular disorders. Oxidative stress has been characterized in such pathogenesis and is an exploitable […]
  • The Role of N-acetylcysteine Amide in Acute Graft-versus-host Disease Mouse Model
    by He, R., Zheng, W., Rozing, K., Moro, C. F., Li, X., Yin, Y., Zhou, W., Andaloussi, S. E., Norgren, S., Zhao, Y., Hassan, M.
    Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic hematopoietic cell transplantation (allo-HCT), resulting in reduced quality of life, morbidity, and mortality in transplanted patients. Clinical strategies to prevent GvHD are frequently associated with off-target effects and dose-related toxicity. Given that oxidative stress is elevated in allo-HCT recipients and contributes to the pathogenesis of GvHD, the current study aims to characterize the role of N-acetylcysteine amide (NACA), a novel antioxidant, as the prophylactic treatment for acute GvHD. Using […]
  • treecompareR: Tree Visualizations of Chemical Space
    by Kruse, P. M., Ring, C. L.
    This paper presents the treecompareR package for R, which provides tools for reproducible visualizations of data through the use of taxonomies. The package builds on developments from ggplot2 and ggtree to provide visualizations tailored for use with taxonomic classification data. Additionally, it provides tools that leverage developments in network analysis to compare data sets. While designed specifically for chemical classification objectives using ClassyFire (http://classyfire.wishartlab.com/), treecompareR also provides tools for use with more general taxonomies. treecompareR is available from GitHub at […]
  • Andrographolide prevents necroptosis by suppressing generation of reactive oxygen species
    by Lu, N., Li, Q., Duan, L.-h., Xu, R., Li, Y.-p., Shi, F.-l., Zhou, Z.-y., Gan, Y.-q., Hu, B., Li, J.-h., He, X.-h., Ouyang, D.-y., Zha, Q.-b.
    Andrographolide (Andro), a natural product extracted from the Chinese traditional medicine herb Andrographis paniculata, has been applied for the treatment of diverse inflammatory diseases. However, its effects on necroptosis, a lytic form of cell death implicated in various inflammatory diseases, remain uncharacterized. In the current research, we investigate whether Andro and its derivatives can suppress necroptosis. The results demonstrate that Andro notably inhibits the necroptosis in in vitro cellular models induced by either lipopolysaccharide (LPS) plus IDN-6556 or a combination […]
  • A Precision Gene Engineered B Cell Medicine Producing Sustained Levels of Active Factor IX for Hemophilia B Therapy
    by Liu, H., Morgan, R. A.
    Hemophilia B gene therapy treatments currently have not addressed the need for predictable, durable, active, and redosable factor IX (FIX). Unlike conventional gene therapy, engineered B Cell Medicines (BCMs) are durable, redosable, and titratable, and thus have the potential to address significant unmet needs in the Hemophilia B treatment paradigm. BE-101 is an autologous BCM comprised of expanded and differentiated B lymphocyte lineage cells genetically engineered ex vivo to secrete FIX-Padua. CRISPR/Cas9 mediated gene editing at the C-C chemokine receptor […]
  • Structure-Based Classification of CRISPR/Cas9 Proteins: A Machine Learning Approach to Elucidating Cas9 Allostery
    by Madugula, S. S., Jayasinghe-Arachchige, V. M., Norgan Radler, C., Wang, S., Liu, J.
    The CRISPR/Cas9 system is a powerful gene-editing tool. Its specificity and stability rely on complex allosteric regulation. Understanding these allosteric regulations is essential for developing high-fidelity Cas9 variants with reduced off-target effects. Here, we introduce a novel structure-based machine learning (ML) approach to systematically identify long-range allosteric networks in Cas9. Our ML model was trained using all available Cas9 structures, ensuring a comprehensive representation of Cas9s structural landscape. We then applied this model to Streptococcus pyogenes Cas9 (SpCas9) to demonstrate […]
  • TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.
    by Riley, S., Vy Nguyen, V., Bhattacharjeec, R., Ng, P. Q., Ritchie, T. C., Fisk, I., Gecz, J., Kumar, R., Searle, I. R.
    {beta}-Cyano-L-alanine (BCA) and {gamma}-glutamyl-{beta}-cyano-L-alanine (GBCA) are the primary antinutritional compounds present within the seeds of the high protein and drought tolerant orphan legume Vicia sativa. Evidence of neurotoxicity is limited to symptom analysis from animal feed trials whilst the molecular mechanisms underlying suspected neurotoxicity in monogastric animals are largely unknown. In this study, we first optimised an in vitro cell-based assay for rapid testing of BCA and GBCA toxicity in the retinoic acid differentiated SH-SY5Y human neuroblastoma cells. Using this […]
  • A Cheminformatics Workflow for Higher-throughput Modeling of Chemical Exposures from Biosolids
    by Kruse, P. M., Ring, C. L.
    The U.S. Environmental Protection Agencys Biosolids Screening Tool can predict potential human and ecological exposures to chemical contaminants in treated sewage sludge biosolids, but large quantities of chemical-specific physico-chemical data are required to parameterize the model. Here, an R workflow is presented that leverages publicly-available databases of chemical information to prepare data for model simulations using the Biosolids Screening Tool. The automated Biosolids Screening Tool workflow (autoBST) reduces the time to gather data necessary to screen hundreds of chemicals from […]
  • PAC: A novel translational concordance framework identifies preclinical seizure models with highest predictive validity for clinical focal onset seizures
    by Anderson, L. L., Kahlig, K. M., Barker-Haliski, M. L., Hannigan, B., Toop, H., Matthews, L. G., French, J., White, H. S., Souza, M., Petrou, S.
    ABSTRACT/SUMMARYO_ST_ABSObjectiveC_ST_ABSCentral to the development of novel antiseizure medications (ASMs) is testing of anticonvulsant activity in preclinical models. While various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS). MethodsThe Praxis Analysis of Concordance (PAC) framework was implemented to assess the translational concordance between preclinical and clinical ASM […]
  • The non-steroidal mineralocorticoid receptor (MR) antagonist (FINERENONE) reverses Western diet-induced kidney disease by enhancing mitochondrial metabolism and decreasing lipid accumulation and inflammation
    by Myakala, K., Wang, X. X., Shults, N. V., Hughes, E., Ribeiro, P. d. C., Penjweini, R., Link, K., Barton, K., Jones, B. A., Krawczyk, E., Clarkson-Paredes, C., Popratiloff, A., Knutson, J. R., cowart, l. a., Levi, M.
    Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Current studies determined the mechanisms of the beneficial kidney effects of the non-steroidal MR antagonist finerenone (FN) in a mouse model of western diet-induced obesity and insulin resistance. 10-week-old male C57BL/6J mice were fed a low fat (LF) or western diet (WD) for 12 weeks followed by treatment with either vehicle or finerenone (FN) for another 14 […]
  • Transcriptomic insights into early diagnosis of doxorubicin-induced cardiotoxicity in a rat model
    by Anca, E., Pavel, I. O., Licarete, E., Rosioru, C., Dobre, C., Banciu, M.
    Doxorubicin is a member of the anthracycline class of chemotherapeutic agents and is among the most effective treatments available up to date. However, its clinical use is significantly limited by severe cardiotoxic effects. The purpose of this study is to investigate the transcriptomic alterations that occur in a rat model of doxorubicin-induced cardiotoxicity. Our results reveal significant dysregulations of cardiac metabolism and provide insights into the molecular mechanisms underlying cardiac damage produced by this treatment. Our analysis revealed that heart […]
  • GM1 and GD3 Gangliosides Attenuate NGF-TrkA and BDNF-TrkB Signaling Dysfunction Associated with Acute Diisopropylfluorophosphate Exposure in Mouse Brain
    by Itokazu, Y., Beck, W. D., Terry, A. V.
    The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. […]
  • ANALYSIS OF PHYTOEXTRACTS OF MEDICINAL PLANTS FOR ANTIMICROBIAL ACTIVITY AGAINST PATHOGENIC STRAINS OF MICROORGANISMS
    by Chokheli, V. A., Butenko, E. V., Pokudina, I. O., Firsova, I. M., Azarov, A. S., Belyaev, M. O., Tsymerskaia, C. A., Sushkova, S. N.
    The study of aqueous and alcoholic phytoextracts of medicinal plants of the Rostov region: wormwood (Artemisia absinthium), thyme (Thymus dimorphus) and sage (Salvia officinalis) for pathogenic strains of Staphylococcus aureus, Klebsiella sp. and Escherichia coli. Various plant organs, such as flower, stem, leaf, and root, were used as phytoextracts. The antibacterial effect was provided by aqueous extracts from the leaves of A. absinthium in relation to S. aureus, as well as extracts of S. officinalis on Klebsiella sp strains. Alcohol […]
  • Restoration of Susceptibility of blaNDM-bearing Escherichia. coli to Carbapenem Antibiotics by Exogenous N-acetylcysteine
    by Li, D., Zhao, Y., Guo, X., Li, C., Sun, Y., Wang, Y., Chang, L., Wang, X., Wang, Y., Schwarz, S., Du, X.-D.
    The global spread of the New Delhi metallo-{beta}-lactamase (NDM) -producing carbapenem-resistant Enterobacteriaceae pose a serious threat to public health, as NDM and its variants enzymes efficiently hydrolyze almost {beta}-lactam antibiotics. The development of novel antibiotics or antibiotic adjuvants capable of eradicating antibiotic-resistance bacteria through multiple mechanisms represents a promising strategy for reversing antibiotic resistance and preventing the emergence of new resistance. In this study, we utilized high-performance liquid chromatography (HPLC) to demonstrate that N-acetylcysteine (NAC) is a prominent reducing metabolite […]
  • Primulagenin A is a potent inverse agonist of the nuclear receptor RAR-related orphan receptor gamma (RORγ)
    by Schwarz, P. F., Perhal, A. F., Preglej, T., Breit, L., Schmetterer, K. G., Grienke, U., Janneschütz, J., Chen, Y., Rochel, N., Kirchmair, J., Schützenmeister, N., Rollinger, J. M., Bonelli, M., Dirsch, V. M.
    Throughout history, herbal medicines and natural products have played a crucial role as therapeutics for humans, yet their molecular mechanisms of action often remain elusive. Here, we ask whether primulagenin A (PGA) from the traditionally used herbal substance Primula root, acts via the nuclear receptor ROR{gamma}, a key regulator of pro-inflammatory Th17 cells, which are linked to autoimmune diseases like psoriasis. Luciferase assays revealed a high potency (IC50 [~]100 nM) and efficacy (Imax [~] 90%) of PGA as an inverse […]
  • Field potential Imaging in human iPSC- derived Cardiomyocytes using UHD-CMOS-MEA
    by Matsuda, N., Nagafuku, N., Matsuda, K., Ishibashi, Y., Taniguchi, T., Matsushita, Y., Miyamoto, N., Yoshinaga, T., Suzuki, I.
    Evaluation using beat propagation analysis of human iPS cardiomyocytes is an effective approach for assessing human cardiac safety in drug development. However, current applications are primarily focused on detecting QT prolongation and arrhythmia risk, while its ability to comprehensively detect cardiotoxicity remains insufficient. Additionally, predicting the mechanism of action, which is crucial in drug development, remains challenging. In this study, we employed field potential imaging (FPI) using an ultra-high-density (UHD) CMOS microelectrode array (MEA) comprising 236,880 electrodes with high spatiotemporal […]
  • Target engagement studies and kinetic live-cell degradation assays enable the systematic characterization of HDAC6 PROTACs at endogenous protein expression levels
    by Hanl, M., Feller, F., Honin, I., Tan, K., Schaeker-Huebner, L., Bueckreiss, N., Schiedel, M., Guetschow, M., Bendas, G., Hansen, F. K.
    Histone deacetylase 6 (HDAC6) is an important drug target for the treatment of cancer, inflammation, and neurodegenerative disorders. In recent years, the development of proteolysis-targeting chimeras (PROTACs) has emerged to achieve the chemical knockdown of HDAC6. Consequently, there is an urgent need to develop efficient methods for target engagement studies and to enable a thorough characterization of the degradation efficiency and kinetics of HDAC6 PROTACs. In this work, we present a simple NanoBRET assay to assess HDAC6 cellular target engagement […]
  • Pregnancy-Dependent Cardioprotection via GPER Activation in Dahl Salt-Sensitive Rats
    by Alencar, A. K. N., Swan, K. F., Manoharan, M. M., Natale, C. A., Lindsey, S. H., Pridjian, G., Garrett, M. R., Bayer, C. L.
    BackgroundPreeclampsia is a hypertensive disorder of pregnancy that affects multiple organs, including the heart, increasing long-term cardiovascular risks for both the mother and offspring. While the G protein-coupled estrogen receptor (GPER) has cardioprotective effects, its role in pregnancy-associated cardiac dysfunction, particularly in chronic hypertension, remains unclear, given the significant physiological adaptations that occur during pregnancy, including hormonal fluctuations and hemodynamic changes. This study investigated whether LNS8801, a selective and orally bioavailable GPER agonist, could improve cardiac function in virgin and […]
  • Targeting therapeutic nanoparticles to the glioblastoma resection margin by harnessing post-operative spatiotemporal blood-brain barrier disruption
    by Fernandes, L. F., Peeyatu, C., Dickie, B. R., Ho, Y. S., Thompson, L. A., Hernandez, N., Lozano, N., Kostarelos, K., Kisby, T.
    Resection surgery is the first-line therapy for glioblastoma (GBM) that is performed in >70% of patients, typically within days of suspected diagnosis. Current protocols for follow-on chemoradiotherapy have shown only modest efficacy in eliminating residual disease, leading to inevitable tumour recurrence. There remains a need for new approaches to swiftly and effectively treat post-operative residual disease to prevent the rapid early progression of recurrent GBM. Using syngeneic preclinical models of glioblastoma resection, we identified a spatially and temporally restricted window […]
  • A computational workflow for assessing drug effects on temporal signaling dynamics reveals robustness in stimulus-specific NFκB signaling
    by Bozich, E. R., Guo, X., Wilson, J. L., Hoffmann, A.
    Single-cell studies of signal transduction have revealed complex temporal dynamics that determine downstream biological function. For example, the stimulus-specific dynamics of the transcription factor NF{kappa}B specify stimulus-specific gene expression programs, and loss of specificity leads to disease. Thus, it is intriguing to consider drugs that may restore signaling specificity in disease contexts, or reduce activity but maintain signaling specificity to avoid unwanted side effects. However, while steady-state dose-response relationships have been the focus of pharmacological studies, there are no established […]

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