- by Wong, M., Martinez, T., Hua, M., Hendricks, N., Talbot, P.Hydroxyacetone has been detected at high concentrations (up to ~12 mg/mL) in electronic cigarette (EC) aerosols, including those derived from products associated with adverse health effects. Given the limited understanding of its inhalation toxicology, we investigated hydroxyacetones impact on human airway epithelial cells. Acute exposures at the air liquid interface (ALI) using 3D EpiAirway tissues, a surrogate for human tracheobronchial epithelium, were analyzed via proteomics. Differential expression analysis identified numerous affected proteins, with enrichment pointing to alterations in mitochondrial function […]
- by Mahadeo, A., Bammler, T. K., MacDonald, J., Zheng, A. R., Yeung, C. K., Himmelfarb, J., Kelly, E. J.Ochratoxin-A (OTA) is a ubiquitous mycotoxin contaminant in food products and a known nephrotoxin that is not currently regulated in the United States. OTA is hypothesized to be a potential environmental agent causing chronic kidney disease of unknown etiology (CKDu), however the mechanism of OTA toxicity in the human kidney remains elusive. This study aims to elucidate OTA-induced molecular toxicological pathways using primary human proximal tubule epithelial cells (PTECs). We demonstrated that exposure to OTA (10 M) induces over 7000 […]
- by Rice, B., Wooton, B., Jansen, C., Howard, J., Nixon, J., Ellis, L., Rogers, A., Adra, C. N., Stokes, A. J., Aporosa, A., Small-Howard, A. L., Turner, H.Phytomedicines have played a vital role in traditional medical systems globally, particularly in providing culturally relevant and accessible healthcare solutions. Piper methysticum, known as Kava, is a traditional Pacific Island phytomedicine with clinically validated anxiolytic properties, primarily attributed to its Kavalactones. However, the biogeographically restricted distribution of Piper methysticum and the ecological and cultural concerns surrounding its widespread adoption highlight the need to explore alternative sources within the Piper genus. This study investigates whether other species within the Piper genus, […]
- by Jin, C., Shi, M., Liu, H., He, S., Zhu, H., Wang, P.Premature ovarian failure (POF) is characterized by disrupted estrous cycles and impaired folliculogenesis due to oxidative stress and inflammation. In this study, a cyclophosphamide (CTX)-induced POF rat model was used to evaluate the protective effects of ergothioneine (EGT) and a nutraceutical formula (FineNutri Cellular Vitality Capsules) containing EGT. CTX treatment markedly prolonged the estrous cycle, reduced estrus duration, decreased ovarian weight, impaired follicular development, and increased granulosa cell apoptosis. Serum estradiol (E2) and anti-Mullerian hormone (AMH) levels decreased, whereas luteinizing […]
- by Chennoufi, M. M., Dridi, D., Lasram, K., Ben Abdeljalil, N., Omezzine, A., Boughattas, N. A.PurposeIfosfamide (IFO), an alkylating anticancer drug, is clinically effective but limited by severe toxicities, notably encephalopathy and urotoxicity. Chronotherapy -optimizing drug delivery according to circadian timing-may improve its therapeutic index and reduce toxicity. This study investigated circadian variation in IFO-induced toxicities in mice. MethodsA total of 160 male Swiss albino mice were synchronized to a 12:12 h light-dark cycle. In an earlier study, IFO chronotolerance assessed at LD50 (a lethal dose to 50 % of mice) showed circadian survival rhythms […]
- by Kalian, A. D., Silva, A. C., Lee, J., Dorne, J.-L. C., Potter, C., Benfenati, E., Osborne, O. J., Guo, M., Hogstrand, C.Novel Quantitative Structure-Activity Relationship (QSAR) models were constructed using Graph Convolutional Networks (GCNs), to predict Drug-Induced Liver Injury (DILI), Drug-Induced Renal Injury (DIRI) and Drug-Induced Cardiotoxicity (DICT) of Selective Androgen Receptor Modulators (SARMs) – an emerging class of performance-enhancing drugs. Prior to training on DILI, DIRI and DICT datasets, the GCN QSAR models were first pre-trained on a variety of unrelated biomedical assay datasets, as an attempt to improve model performance via transfer learning. The success of the transfer learning […]
- by Badhe, P.Artificial intelligence-assisted scientific prompting is reshaping how biological targets can be rapidly identified and contextualized. In this work, we present the Swalife PromptStudio – Target Identification workflow and illustrate its application to poly(ADP-ribose) polymerase-1 (PARP1), a central regulator of DNA repair and genome integrity. Using structured prompts, we systematically explored literature, pathway databases, and genetic repositories to compile a multi-dimensional profile of PARP1. Prompt-guided mining revealed strong associations with base-excision repair, single-strand break repair, and homologous recombination pathways, positioning PARP1 […]
- Exploratory Assessment of Preconception Phthalate Exposure on Fertility and Offspring Health in Miceby Afghah, M., Elkins, A. C., Powell, P. C., Mulligan, M. E., Boland, M. C., Suggs, A. P., Walker, M. A., Padgett, Z. J., Rock, K. D.Infertility affects 10-15% of couples worldwide and is increasingly attributed to environmental exposures, particularly endocrine-disrupting chemicals (EDCs) such as phthalates. While gestational exposures are well studied, little is known about how preconception exposures influence fertility and offspring health. Phthalate exposure altered estrous cyclicity, with dams spending more time in proestrus and less in metestrus but did not significantly impact implantation or litter size. At E14.5, exposed fetuses exhibited increased bodyweights, accompanied by an expansion of the placental junctional zone in […]
- by Cho, S., El gaamouch, F., Upadhyay, S., Nada, H., Kuncewicz, K., Gabr, M.Triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction contributes to Alzheimers disease pathogenesis, yet current therapeutics cannot prevent ADAM-mediated receptor shedding that diminishes signaling efficacy. Using Affinity Selection-Mass Spectrometry (AS-MS) screening, we identified As48, a novel small molecule that binds TREM2 with high affinity. Biophysical validation confirmed s 7-fold selectivity over TREM1. Cellular assays demonstrated that As48 functions as a TREM2 agonist, activating SYK phosphorylation and enhancing microglial phagocytosis. Molecular docking and molecular dynamics simulations revealed that As48 binds […]
- by Trottiet, J., Lavoie, A.-A., Verreault, M., Wunsch, E., Straka, R. J., Ghonem, N., Milkiewicz, P., Barbier, O.Glucuronidation is a detoxification reaction for bile acids (BA). The present study evaluates its efficiency to protect liver cells during acute (biliary obstruction, BO) and chronic (primary biliary cholangitis, PBC and primary sclerosing cholangitis, PSC) cholestatic situations. BA-glucuronides (G) were first profiled in sera from control, PBC, PSC and BO donors. An impressive accumulation of BA-Gs, formed from toxic BAs, is observed in sera from BO patients. Liver samples from control, PBC, or PSC donors and human hepatic cells were […]
- by Marin-Toledo, J. P., Greenan, D. M., Celis, N., Haske, L., Lewandowska, A., Rakowski, C. K., Shastry, S., Maji, A., Green, K. J., Pogorelov, T. V., Welsh, M. J., Thornell, I. M., Burke, M. D.The ion channel-forming natural product amphotericin B (AmB) can serve as a molecular prosthetic for the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel and thereby restore host defenses in cultured cystic fibrosis (CF) airway epithelia. This is despite the fact that the permeability of AmB-based channels favors cations, and these channels lose their capacity to increase airway surface liquid (ASL) pH in CF airway epithelia at high concentrations. We hypothesize that modifying such channels to favor anion permeability would […]
- by Cho, S., Kaur, B., Lam, K., El gaamouch, F., Kuncewicz, K., Doering, N., Wolber, G., Gabr, M.Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose activation promotes phagocytosis and neuroprotection in Alzheimers disease (AD) and related neurodegenerative disorders. While therapeutic efforts have largely focused on antibodies, small molecule TREM2 modulators remain limited. Here, we applied a structure- based virtual screening workflow targeting a putative allosteric site on TREM2, guided by PyRod-derived pharmacophores from molecular dynamics simulations. Screening of the Enamine Collection yielded 20 candidate compounds, three of which demonstrated binding in TRIC […]
- by Patel, N. M., Sivaramakrishnan, S.Glucose-dependent insulinotropic peptide receptor (GIPR) stimulates insulin release and regulates metabolic homeostasis. GIPR function is shaped by spatiotemporal trafficking of this G protein-coupled receptor (GPCR). While GPCR endocytosis is traditionally associated with {beta}-arrestin, GIPR internalization is only modestly dependent on this pathway. In this study, we demonstrate that GIPR engages a cytoskeletal motor, myosin VI to drive receptor endocytosis. GIPR engages the adaptor-motor complex through a PDZ-binding motif (PBM) at its C-ail. Interestingly, {beta}-arrestin binding to phosphorylated residues upstream of […]
- by Liao, G. Y., Klug, J., Dai, S., Singh, S., Bae, E., Ladiges, W. C.The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were […]
- by Niemeijer, M., Wolters, L., ter Braak, B., Patel, H., Sharma, R., Nicol, B., Sparman, C., Hatherell, S., Middleton, A., White, A., Beltman, J., van de Water, B.The activation of stress responses upon chemical exposure is critical to restore cellular homeostasis. One of these pivotal pathways is the oxidative stress response activated by NRF2 under control of sensor KEAP1. Soft electrophiles are known to bind with KEAP1 and consequently activate NRF2. However, the understanding of the NRF2 activation dynamics and influence on cellular fate during prolonged repeated exposure conditions is still lacking. Therefore, we accurately mapped the NRF2 activation dynamics upon single or repeated exposures using HepG2 […]
- by Kiani, L. N., Civiletto, G., Lizzo, G., Zdebik, A., Brickell, G., Mahmood, F., Nalkos, D. D., Michaelides, L., Eldridge, P., Young, E. M., McPherson, H., Campanella, M., Gut, P., Russell, C.Lysosomal storage disorders (LSDs), a group of inherited genetic diseases, are often associated with early-onset neurodegeneration and refractory epileptic seizures. In CLN2 disease, an LSD caused by recessively inherited dysfunction of lysosomal serine protease Tripeptidyl Peptidase 1 (TPP1), lysosomes are functionally impaired through a characteristic accumulation of subcellular materials. Here, we develop and apply a whole-organism screening workflow in tpp1-/- zebrafish to identify small molecules that suppress epileptic seizures — a hallmark of the human disease — in this model. […]
- by Bouftas, N., van Duursen, M. B. M.There is a high need for accepted test methods for chemicals that affect the hormonal system, also known as endocrine disruptors (EDCs). The H295R adrenal cell line is considered the gold standard for investigating chemicals that can disrupt steroidogenesis. This method is described in test guideline 456, established by the Organisation for Economic Co-operation and Development (OECD), and currently focuses only on changes in testosterone (T) and estradiol (E2). However, the culture media from H295R cells contains a wide range […]
- by Zhang, L., Nada, H., Gabr, M.Chitinase-3-like 1 (CHI3L1) is a secreted glycoprotein implicated in carcinogenesis and tumor immune evasion. Elevated CHI3L1 expression is frequently detected in cancer patients, highlighting it as a promising therapeutic target. To overcome the limited availability of small molecule CHI3L1 inhibitors, we established a surface plasmon resonance (SPR)-based high-throughput screening platform and applied it to a focused chemical library of small molecules. Primary screening identified seven hits, with compounds 1-4 and 1-7 validated as CHI3L1 binders (Kd = 10.4 {+/-} 1.0 […]
- by Yoneda, S., Uta, D., Yasufuku, K., Yamane, T., Yoshioka, S., Takasu, K., Izumi, T., Fujita, S., Nakamori, D., Kawasaki, S., Takahashi, T., Yoshikawa, M., Ogawa, K., Kasai, E.Neuropathic pain remains difficult to treat effectively because of the limitations of current pain medications. The Nav1.7 sodium channel plays a crucial role in pain sensation. The development of selective inhibitors has been challenging because of the high similarity among Nav channel subtypes. To address this issue, we developed monoclonal antibodies that selectively target Nav1.7 and humanized them for clinical use for the first time. When administered systemically to neuropathic pain model rats, a potent analgesic effect was observed that […]
- by Singh, A. K., Gardner, Z. S., Kumpati, G. P., Jacob, M., Ronayne, C. T., Mereddy, V. R.Reprogrammed mitochondrial metabolism is recognized as an important target for anticancer therapy. Niclosamide, an FDA approved anthelmintic agent with mitochondrial uncoupling activity, has shown promise as an anticancer agent. However, off target mitochondrial toxicity has rendered the utility of this agent at clinically effective doses. Here, we synthesize a variety of prodrugs on the niclosamide template based on the Baylis-Hillman (BH) reaction, with the hypothesis that niclosamide will be released upon the reaction with cellular nucleophiles, including thiols. Consistent with […]
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