- by Liugaila, A., Mitchell, R. T., Gadd, A., Duffin, K., Stefansdottir, A.Objective Sodium valproate (SV) is a widely used anti-epileptic drug with well-established reproductive and teratogenic effects, yet its impact on the developing prepubertal reproductive system remains poorly understood. This study investigated the effects of prepubertal SV exposure on gonadal development, including folliculogenesis, testicular architecture and steroidogenic gene expression in male and female mice in vivo. Methods CD1 mouse pups received intraperitoneal injections of saline (control), low or high dose SV (50 or 100 mg/kg, respectively) on postnatal days (PND) 6, […]
- by Pohjavaara, S. A., Majid, Q. A., Huttunen, L., Aalto-Setälä, K., Ruskoaho, H., Välimäki, M. J., Kinnunen, S. M., Talman, V.Background Hypertrophic and dilated cardiomyopathies (HCM and DCM) are the most common inherited cardiomyopathies. However, genotype-specific molecular and functional cardiomyocyte phenotypes and responses to neurohormonal stimulation remain incompletely understood. Here, we investigated whether patient-derived HCM and DCM cardiomyocytes exhibit distinct baseline phenotypes or differential responses to hypertrophic stimulation and pharmacological treatment. Methods Three human-induced pluripotent stem cell (hiPSC) lines were used: a control line, an HCM patient-derived line carrying a MYBPC3 mutation, and a DCM patient-derived line carrying an LMNA […]
- by Boora, T. S., Chen, H., Cho, A., van der Velden, W. J. C., Namkung, Y., Cao, Y., Paranjpe, J. Y., Heydenreich, F. M., RODIN, A. S., Branciamore, S., Vaidehi, N., Laporte, S.G protein-coupled receptors (GPCRs) regulate diverse physiological responses by engaging distinct heterotrimeric G proteins, yet the basis of G selectivity in promiscuous receptors remains unclear. Although ligand bias holds therapeutic promise, selectivity has been assumed to reside mainly in the ligand-binding site (LBS) or G protein interface (GPI). Here, we combine whole-receptor mutagenesis, functional G protein assays, molecular dynamics simulations, interpretable machine learning method, and Bayesian network modeling to identify residue networks governing Gq/11 and G12/13 coupling and to define […]
- by Roudi, S., Estupinan, H. Y., Saher, O., Barradas, C., Inganas, E., Le, H.-N., Frengen, N., Grochowski, R., Pavlova, S., Mansson Welinder, R., Nordin, J. Z., Biscans, A., Matsson, P., Zain, R., Sandberg, R., Hagemann-Jensen, M., EL Andaloussi, S.Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a […]
- by Zhang, H., Liu, Y., He, F., Xue, G., Kang, Y., Zhang, Z., Ma, J., Xiao, J., Meng, Q.Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, […]
- by Sultana, J., Castano, J. D., del Castillo, J. R. E., Beaudry, F.Gabapentin (GBP) and pregabalin (PGB) are widely used gabapentinoids. Previously, we have demonstrated, for the first time, that GBP and PGB modulate the nociceptive response to noxious heat in C. elegans at an optimal concentration. In the current study, we use C. elegans and paired thermal nociception assays with direct internal drug concentration measurements to characterize the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of both compounds. Neither drug altered baseline mobility or quadrant preference, confirming that behavioral effects reflected genuine antinociceptive action. […]
- by Thomas, M. E., McLean, Z. S., Belcher, S. M.Per-and polyfluoroalkyl substances (PFAS) constitute a diverse class of persistent synthetic chemicals utilized across industrial, medical, and consumer sectors that are pervasive global pollutants. Exposure to PFAS is linked to adverse impacts on both innate and adaptive immune systems. Human lactoferrin (hLF) is a key antimicrobial component of the developing innate immune system present in colostrum and breast milk. We hypothesized that hLF is a potential PFAS binding protein related to PFAS immunotoxicity. The results of thermal stability experiments indicated […]
- by Liu, D., Williams, P. D., Kimber, M. J., Robertson, A., Martin, R. J.Ivermectin is an important broad-spectrum anthelmintic used to treat nematode parasites including gastro-intestinal infections of humans and animals. The mode of action for Ivermectin is understood to involve activation of inhibitory glutamate-gated chloride channels (GluCls). Ivermectin has also been reported to inhibit the release of extracellular vesicles (EVs). We found that EVs are released from the whole intestine of the gastro-intestinal parasite, Ascaris suum. Proteomic analysis identified 1,574 proteins within these intestinal EVs, including 96 nematode proteins with putative immune-associated […]
- by Leheup, M. F., Johnson, G., Kirkland, D., Pasello dos Santos, F., Mueller, S., Weaver, R., Griffon, A.The presence of N-nitrosamine drug substance-related impurities (NDSRIs) in pharmaceuticals represents a significant regulatory and safety challenge due to their classification as "cohort of concern" compounds. This paper describes the toxicological evaluation of N-Nitrosotrimetazidine (NTMZ), performed to refine the initial default acceptable intake (AI) limits of 18 to 26.5 ng/day established by regulatory authorities. The evaluation followed a tiered approach: NTMZ was first confirmed as mutagenic in vitro via the standard Ames test. To further investigate its genotoxic potential, two […]
- by Nael, M. A., Alakonda, L. M., Gianti, E., Elokely, K.Peroxiredoxins protect cells from oxidative damage, and sulfiredoxin (Srx) restores their activity by repairing the overoxidized catalytic cysteine; how the two proteins recognize one another is central to redox signaling and to oxidative-stress-associated disease. We characterize the human peroxiredoxin-1 (PRDX1)-Srx repair intermediate (PDB 2RII) and four related catalytic-cysteine states by all-atom molecular dynamics (three replicas of 200 ns per system; 3.0 microsecond total), using geometric and kinetic observables only, with across-replica statistics. The disulfide-linked complex is stable (backbone RMSD 2.5- […]
- by Wager-Miller, J. B., Szanda, G., Straiker, A., Bosire, K., Mackie, K.We published recently that one of the main constituents of cannabis products, cannabidiol (CBD), is an efficacious negative allosteric modulator (NAM) of the mu opioid receptor (MOR1) (Bosquez-Berger et al., 2023). Here, we investigated how the presence of cannabidiol (CBD) is associated with fentanyl (FEN) binding across MOR1 conformations. We performed molecular dynamics simulations of systems containing FEN alone or FEN+CBD in three mouse MOR1 conformational backgrounds: active-like 5C1M, inactive-like 4DKL, and a modeled Morph50 intermediate between the 5C1M and […]
- by Cooper, A. J., Tabman, J. S., Rodriguez, R., Bhattacharjee, A.Introduction: Osteoarthritis (OA) is a degenerative joint condition characterized by chronic pain and the need for pain management. Locally targeting the endocytotic AP2 complex in nociceptors presents a potential strategy for providing sustained pain relief in individuals with OA. Objective: We investigated whether pain behavior associated with OA can be mitigated by genetically silencing the AP2alpha2 subunit of the AP2 complex in nociceptors and by pharmacologically inhibiting the AP2 complex through the intraarticular administration of a small lipidated decoy peptide. […]
- by Taffe, M. A., Kim, H. S., Doran, T. A., Coons, T. R., Rahman, S. R., Grant, Y., Vandewater, S. A.Background: The nicotine analog 6-methyl nicotine (6-MN) has appeared in commercial e-cigarette liquids, and other products, spurring interest in determining the extent to which it conveys similar effects to those of nicotine. Objective: To determine if 6-MN acts like nicotine to decrease body temperature, decrease nociception, suppress wheel activity and reinforce operant behavior when delivered by vapor inhalation using an Electronic Nicotine Delivery System (ENDS; "e-cigarette") approach in a rat model. Methods: Male and female (N=8 per sex) young adult […]
- by von Hacht, L., Meier, T., Ridder, J., Schrapers, J., Afflerbach, A.-K., Hirt, M., Hansen, A., Kirchhof, P., Eschenhagen, T., Stenzig, J., Fabritz, L., Sommerfeld, L. C.Background: Atrial fibrillation (AF) burden is increasingly recognized as a determinant of clinical risk. Currently, AF burden can only be estimated using long-term rhythm monitoring. Bone morphogenetic protein 10 (BMP10) is a protein secreted from cardiac atria associated with AF and AF-related complications. This study evaluated whether BMP10 concentrations are associated with AF burden in a human atrial model: atrial engineered heart tissue (aEHT). Methods: Human induced pluripotent stem cell-derived atrial cardiomyocytes were cast into atrial engineered heart tissues (aEHTs). […]
- by Kaminaga, H., Sajjaviriya, C., Azuma, M., Kashiwakura, Y., Niwa, F., Tsuchiya, H., Ohmori, T., Koshimizu, T.-a.How water intake is initiated and maintained following V2 vasopressin receptor antagonism remains poorly understood. To elucidate the role of the V1b receptor in managing dehydration stress induced by V2 antagonism, we used deep learning-based computer vision to analyze drinking behavior in V1b knockout (V1bKO) and wild-type (WT) mice. While total water access and intake volume were comparable between genotypes, V1bKO mice exhibited distinct temporal dynamics. Modeling cumulative intake with the Hill equation revealed that the time required to reach […]
- by Jabba, S. V., Li, Z., Jordt, S. E.Background: In the United States, several states have restricted sales of flavoured tobacco products, including popular menthol- and mint-flavoured Oral Nicotine Pouches (ONP). In response, tobacco companies introduced "unflavoured" ONP containing odorless synthetic cooling agents. Since these, in turn, have become targets of legislative bans, the tobacco industry may seek out flavourants with other sensory effects to increase the appeal of "unflavoured" ONP. Methods: Online merchants were searched for "unflavored" ONP marketed to consumers in jurisdictions with flavour bans. Sensory […]
- by Nael, M. A., Elokely, K.Background: Subtype-selectivity predictions are scored against measured selectivity and judged against an assumed noise ceiling. We asked what an 2-adrenergic benchmark rewards and which controls change its interpretation. Research design and methods: On a frozen benchmark of 586 paired 2A/2C compounds we evaluated Glide SP docking, CNN rescoring, ligand-only fingerprint models, receptor descriptors and pose contacts, with dopamine D3/D2 as comparator, applying five controls: a measured ceiling, a cluster-identity null, a nonselective reference, a same-receptor floor and a trivial-descriptor baseline. […]
- by Bassiouni, W., Abdelnaby, M., Ai, E.-H., Abd-Elrahman, K. S.Alzheimer's disease is characterized by progressive cognitive decline and early cerebrovascular dysfunction, including impaired neurovascular coupling (NVC) and reduced cerebral blood flow (CBF). Tau pathology is a major driver of these deficits, yet therapeutic strategies targeting tau-induced neurovascular dysfunction remain limited. The M1 muscarinic acetylcholine receptor (M1 mAChR) is a promising therapeutic target because of its critical role in cognition. We previously demonstrated that pharmacological activation of M1 mAChR improves cognitive function and neuronal survival in amyloid-based Alzheimer's disease mouse […]
- by Henseler, D., Aruna, O. A.2,4-Dinitrochlorobenzene (DNCB) is a well-characterized skin sensitizer that has been widely used in immunological and toxicological research and, historically, in clinical immunotherapy. Although it is a well-investigated chemical, this is the first study focusing on the dose response behavior at low-level concentrations. The aim was to reveal potential hormetic effects due to its known Nrf2 inducting activity. Therefore, THP-1 cells were treated with low doses of DNCB and two endpoints were evaluated for hormetic responses: metabolic activity using a resazurin-based […]
- by Ledue, E. L., Adelman, N. E., Lorenger, M. K., Wagner, D. J., Trafton, S. K., Biro, E., Morrison, E. R., D'Alessio, Q. W., Burnell, J. E., Gosse, J. A.People are widely exposed to the antimicrobial cetylpyridinium chloride (CPC) via consumer products, but CPC is a mitochondrial toxicant with potency comparable to that of canonical mitotoxicants. CPC is largely unregulated despite growing usage, bioavailability, and ability to cross the blood-brain barrier. Previously, we showed, in several cell types at non-cytotoxic and exposure-relevant doses, CPC inhibits ATP and OCR, endpoints of the electron transport chain (ETC). Mitochondrial toxicity is linked to multiple diseases (e.g., diabetes, Parkinsons, myalgic encephalomyelitis), but CPC […]
Mass spectrometry websites, social media, journal feeds, and other links and items of interest to the mass spectrometry community.
