- by Natesan Sambath, H., Vitsupakorn, S., Sreerama Reddy, K., Brown, L., Nguyen Thi Mai, T., Burke, M., Liu, J., Evans, E., Giamberardino, C., Perfect, J., Ngo Thi, H., Le, T.Background: Talaromyces marneffei causes talaromycosis, a life-threatening fungal disease with limited treatment options. The standard treatment of amphotericin B (AmB) induction followed by itraconazole consolidation still results in 15% to 30% mortality. This study aimed to investigate the potential of AmB and flucytosine (5FC) combination therapy to enhance antifungal activity. Methods: The in vitro antifungal activity of AmB and 5FC alone and in combination against 60 T. marneffei clinical isolates was evaluated using a validated colorimetric antifungal susceptibility assay and […]
- by Wiltse, B., Mattes, B., Navitsky, C., Chakraborty, S., Stager, J. C., Buell, E., Rose, K. C.Florpyrauxifen-benzyl (FPB) is a recently registered arylpicolinate herbicide used to control dicots including Eurasian watermilfoil (EWM). Laboratory studies indicate rapid degradation of FPB in water, but sediment persistence in aquatic systems remains poorly understood, creating uncertainty in ecological risk assessments. We evaluated the environmental fate and transport of FPB and its degradants in water, plants, and sediment following application of the herbicide to two bays of Lake George, NY. FPB was rapidly lost from the water column within 72 hours, […]
- by Lungu-Mitea, S., Stein Aslund, M., Reichstein, I., Pinto-Vidal, F. A., Schiwy, A., Hollert, H., Jacobs, M., Hilscherova, K.Incorporating biotransformation capabilities into in vitro assays represents one of the most critical challenges in toxicology, facilitating the transition from in vivo models to integrated in vitro strategies. Although emerging technologies show promise, their current limitations in scalability hinder high-throughput applications. In the short to mid-term, externally added biotransformation systems (BTS: S9 and microsomal liver fractions) used together with in vitro assays offer viable alternatives. However, despite over fifty years of use, BTS are marred by reproducibility issues, raising concerns […]
- by Yaman, M., Su, H., Lee, J. K., Ferguson, A. C., Sowell, K. M., Xun, J., Wu, D., Habiger, C. J., Hanauer, D. A., Clasby, M. C., Rech, J. C., Shavit, J. A.Venous thromboembolism (VTE) is a highly prevalent medical condition with limited therapeutic options and an incomplete understanding of its acquired and inherited subtypes. The zebrafish is a model with the benefits of external development, fecundity, optical transparency, and hemostasis that demonstrates conservation with mammals. We utilized zebrafish as a phenotypic screening tool to identify novel therapeutic options for preventing VTE. A library of FDA-approved compounds was screened for suppression of acquired (elevated estrogen) and spontaneous (protein C deficiency) thrombosis. We […]
- by Zhao, A. H., Koganti, P. P., Qian, M., Garcia, A., O'Day, P., Auchus, R. J., Covey, D. F., Selvaraj, V.The mitochondrial translocator protein (TSPO) was once proposed to mediate mitochondrial cholesterol import for steroid hormone biosynthesis, but genetic deletion studies in multiple models have refuted this role. Nevertheless, the idea that pharmacological ligands of TSPO can modulate steroid output continues to be invoked. One such compound, 19-Atriol (androst-5-ene-3{beta},17{beta},19-triol), was reported to inhibit progesterone synthesis via TSPO binding in MA-10 Leydig cells. To evaluate this proposed mechanism, we used CRISPR/Cas9-generated Tspo-deleted MA-10 cells to study 19-Atriol activity. We found that […]
- by Liu, X., Franco, E. J., Avedissian, S. N., Hanrahan, K. C., Guedj, J., van Hasselt, J. G. C., Brown, A. N., Martson, A.-G.The timing of initiation is critical in antiviral treatment and viral dynamic (VD) modeling is a powerful tool to study the within-host viral load changes and evaluate antiviral treatment effects using mathematical equations. Previous simulation studies have shown that early treatment initiation is critical to maximize the therapeutic response in antiviral treatment in an acute viral infection such as influenza and SARS-CoV-2. A recent experimental study demonstrated that late therapy initiation can lead to diminished antiviral potency. However, most VD […]
- by Chen, J.-L.Between 2020 and 2023, rising global temperatures and extreme weather events have significantly increased fire incidents, releasing toxic smoke containing lethal cyanide gas. Cyanide disrupts cellular respiration and poses severe risks to victims and first responders. This study quantifies cyanide concentrations in fire smoke and evaluates the antidotal efficacy of hydroxocobalamin. Using a smoke chamber calibrated to 100 ppm cyanide, treated mice demonstrated a 70% survival rate compared to 30% in controls, with median survival times of 12 and 5 […]
- by HUO, W., Qu, J., Wang, S., He, M., Zeng, Z., Kong, D., Yuan, L., Feng, R.Polyethylene terephthalate microplastics (PET-MPs), a major microplastics component identified in human vasculature, pose emerging environmental health risks. This study systemically profiled MPs in human aortic tissues and investigated the mechanisms underlying PET-MPs-induced aortic injury in vivo and in vitro. Chronic oral exposure of Sprague-Dawley rats to PET-MPs (1.0-100 mg/L) resulted in endothelial glycocalyx loss and structural impairment of aortic elastic fibers, with MPs accumulating within aortic endothelial cells. Transcriptomic and biochemical analyses revealed that PET-MPs triggered endoplasmic reticulum stress (ERS) […]
- by Douglass, E. F., Joshi, C., Paez, T., Hughes, E. A., Hannan, E.Traditional laboratory methods quantify drug-efficacy based on dose-response metrics (e.g. IC50 or AUC), whereas clinical oncology defines drug-efficacy based on time-response metrics (e.g. progressive or stable disease). These measures often diverge, limiting translation between bench and bedside. We developed NCI1970-Meta, a harmonized dataset of 49,002 evaluable patients covering 30 drugs and 18 cancers, to provide the first large-scale benchmark linking in vitro potency, clinical pharmacokinetics, and Phase 2-3 outcomes data. Raw in vitro metrics values showed poor correlation with clinical […]
- by Wang, B., ZHAO, L., Yang, J., Liu, T., Cao, H., Yu, M.Objective: This study aims to systematically investigate the molecular mechanisms through which parabens may contribute to head and neck squamous cell carcinoma (HNSCC) carcinogenesis using integrated network toxicology and molecular docking. Materials and Methods: Six commonly used parabens (ethyl-, propyl-, methyl-, heptyl-, butyl-, and benzylparaben) were selected for toxicity prediction via ProTox 3.0 and ADMETlab2.0. Their potential targets were retrieved from Swiss Target Prediction, ChEMBL, and the Similarity Ensemble Approach (SEA). HNSCC-related targets were collected from GeneCards, OMIM, and CTD, […]
- by Urwyler, M., Korsos, M., Dupuychaffray, E., Ascencao, K., Petrosino, M., Zuhra, K., Tachet, J., Purwar, P., Alvarez, M., Pommier, A., Gad, M., Abdelkader, R., Szabo, C., Bourquin, C.Hydrogen sulfide (H2S) is a redox-active gasotransmitter implicated in tumor progression and immune regulation. The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is a key contributor to endogenous H2S and polysulfide production, but its role in tumor-immune interactions remains poorly defined. Here, we show that 3-MST is the most abundantly expressed H2S-synthesizing enzyme in human renal cell carcinoma cells (RCC) and that high 3-MST expression correlates with reduced patient survival. Pharmacological inhibition of 3-MST lowered intracellular H2S levels in Renca renal carcinoma cells, […]
- by Coghlan, H., Williams, D. P., Jones, A., Regan, S., Chouhan, B., Copple, I. M.Cellular stress response pathways such as the NRF2 oxidative stress response, endoplasmic reticulum (ER) stress response and macroautophagy afford protection against many forms of drug toxicity, including the liver toxicity associated with the formation of reactive drug metabolites. To maximise the translatability of preclinical toxicology studies, an understanding of the relative hepatic stress response capacities of humans and widely-used preclinical animal species is vital. In control liver tissue, the basal gene and protein expression of stress response pathway components was […]
- by Cho, S., Zhu, R., Kuncewicz, K., Duan, H., Gabr, M.Triggering receptor expressed on myeloid cells 2 (TREM2) plays a central role in regulating microglial function in the central nervous system and has emerged as a promising therapeutic target for Alzheimers disease. Despite advances in antibody-based therapeutics, small molecules and peptides capable of modulating TREM2 remain limited. Here, we present a cyclic peptide design pipeline that integrates CycleRFdiffusion, ProteinMPNN for sequence design, and HighFold for structural prediction and screening. Using the TREM2 structure as input, we generated and screened 1,500 […]
- by Lai, H., Goldade, M., Keller, S. A., Worms, I., Luciani, A., Neuhauss, S. C. F., Slaveykova, V. I., Devuyst, O., Chen, Z.An efficient endo-lysosomal pathway is crucial to mediate the reabsorption and processing of ultrafiltered solutes including low-molecular-weight (LMW) proteins by the epithelial cells lining the proximal tubule (PT) of the kidney. The zebrafish pronephros is increasingly used as a model system for congenital or acquired disorders that impair the endocytic uptake in PT cells, that cause an inappropriate loss of solutes and LMW proteins in the urine. Here, we describe a new reporter zebrafish line, termed[1/2] vdbp-NanoLuc, in which the […]
- by Thouverey, C., Badoud, I., Ammann, P.To optimize osteoporosis therapy with the parathyroid hormone fragment teriparatide (PTH1-34), we sought to determine whether strontium (Sr) could potentiate bone anabolic action of intermittent PTH1-34 in ovariectomized rats. Female rats were either Sham-operated or ovariectomized (Ovx) at 6 months of age. 8 weeks after operations, Ovx rats received either vehicle solutions, 625 mg/kg/day Sr (5 days per week), 8 {micro}g/kg/day PTH1-34 (5 days per week), or both combined treatments for 8 weeks. PTH1-34 treatment totally reversed the deleterious effects […]
- by Lopez Rodriguez, D., Guerrero Limon, G., Chevre, N.With over 350000 chemicals and mixtures currently registered for production and use worldwide, up to 90% of authorized chemicals lack adequate toxicity data, leaving the majority of chemicals poorly characterized. International agencies urge scientists to develop screening methods to explore, identify, and predict chemical hazards, supporting the prioritization of chemical risk assessment. Here, Tree Manifold Approximation and Projection (TMAP) were applied, with the aim of reducing the dimensionality of large toxicological dataset, providing the foundations to data imputation methods allowing […]
- by Hidalgo-Avendano, D., Pitot Alvarez, C. R., Hurtado Ollero, S. S., Flores Velasquez, X., Surco Quispe, A., Marin Gonzales, A., Aguilar-Olano, J.The climacteric and menopausal transitions involve significant hormonal and physiological changes that impact womens health. During the postmenopausal period, various changes have been documented, including atrophy of the vaginal mucosa and a chronic low-grade inflammatory state, particularly affecting the vaginal mucosa, which contributes to symptomatic deterioration and reduced quality of life. In this study, a chitosan-based polymeric gel was used as a delivery matrix for natural compounds, such as growth factors derived from platelet-rich plasma (PRP) and a hydroalcoholic extract […]
- by Li, Y., Zhao, T., Song, Z., Zhou, X., Martinez Pardo, P., Chen, J., Hu, Q., Li, C., Li, X., Sun, Z., Gao, Y., Hoyle, D. E., Patel, J. S., Elmore, C. S., Yuan, H., Liang, S. H.O-GlcNAcase (OGA) is a glycoside hydrolase that regulates protein O-GlcNAcylation, a dynamic post-translational modification implicated in numerous cellular processes. Dysregulation of OGA alters cellular O-GlcNAc homeostasis and has been linked to neurodegenerative and other chronic diseases. The development of radioligands targeting OGA, particularly those derived from well-characterized tool compounds, could substantially advance drug discovery in this area. Herein, we report the radiosynthesis of a novel tritium (3H)-labeled radioligand 7 (code name [3H]OGA-2506) derived from a chiral piperidine scaffold, and its […]
- Validation of a Microsampling-Compatible LC-MS/MS Method for Cannabinoid Quantitation in Whole Bloodby Mohammed, A. A., Khan, M., Chan, H., Brubacher, J. R.Recently developed dried blood sampling methods for cannabinoid quantitation require small blood volumes, making them microsampling-compatible, but have notable limitations including hematocrit-related bias for dried blood spots (DBS) and higher consumable costs for volumetric absorptive microsampling (VAMS(R)). To address these issues, we developed a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of quantifying cannabinoids in 50 {micro}L of liquid whole blood, providing a practical microsampling alternative to dried blood approaches. Using liquid-liquid extraction (LLE) with sodium hydroxide alkalinization […]
- by Niu, K., Hong, Y., Yuan, M., Zhang, H., Meng, H., Yang, W., Yuan, C., Wang, Y., Xu, H., Zhou, J., Zhang, l.ObjectivesIn this study, the anti-HSV-1 effects of TED were investigated in vitro and in vivo, its therapeutic efficacy against herpetic stromal keratitis (HSK) was evaluated, and its mechanism of action was examined. MethodsWe assessed the cytotoxicity and anti-HSV-1 activity of TED in Vero cells using CCK-8 and plaque assays. The HSK model mice received TED (2.5, 5, or 15 mg/kg), and symptom progression was monitored. The therapeutic effects were evaluated through HE staining, corneal immunofluorescence, and HSV-1 gB quantification. Mechanistic […]
Mass spectrometry websites, social media, journal feeds, and other links and items of interest to the mass spectrometry community.
