- by Fiore, C. M., Agarwal, S. R., Elasoru, S. E., Ardell, J., Ajijola, O., Shivkumar, K., Harvey, R. D.Neuropeptide Y (NPY) is a co-transmitter released from sympathetic neurons along with norepinephrine (NE). It has been observed that cardiac NPY levels are significantly elevated following myocardial infarction (MI), and this has been linked to an increase in ventricular arrhythmogenicity associated with elevated sympathetic tone. However, the effects that NPY has on the electrical activity of ventricular myocytes remain poorly understood. Previous studies have examined the influence of NPY alone on cardiac ion channel function, but not in the presence […]
- by Tsang, Y. P., Wang, K., Kelly, E. J., Mao, Q., Unadkat, J. D.Introduction Infection and inflammation elevate circulating pro-inflammatory cytokines that can affect renal drug clearance. Accordingly, we sought to (i) quantify the extent of modulation of renal drug-metabolizing enzymes and transporters (DMETs) by cytokines and (ii) identify the mechanism(s) underlying these effects. Methods Fresh primary human proximal tubular epithelial cells (PTECs) were cultured on extracellular matrix-coated Transwells. PTECs were exposed every 24 h, for 48 h, to IL-6, IL-1{beta}, TNF-, IFN-{gamma}, IL-4, or IL-10 (0.1 or 1 ng/mL), individually or as […]
- by Retamal, J. S., Peng, S., Nguyen, T.-N., Bandala-Sanchez, E., Eriksson, E. M., McCague, R. E., Mahdavian, N. S., Carbone, S. E., Cao, E., Gondin, A. B., Veldhuis, N. A., Poole, D. P.Background. The control of lymphatic permeability and flow is essential for homeostatic regulation of tissue fluid balance and immune responses. Histamine has been identified as an important signaling mediator involved in the regulation of lymphatic function. Histamine is released from activated perilymphatic mast cells and may also be produced by lymphatic endothelial cells (LECs) in response to flow-induced shear stress. The non-selective cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) is an important mediator of signaling by GPCRs, including histamine […]
- by de la Pena, I., Andino, S., Amis, A., Alkhatib, M. A., Li, T., Keck, T. M., Boateng, C. A.RationaleDopamine D4 receptors (D4Rs) have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD), yet their precise role and therapeutic relevance remain underexplored. Highly selective D4R compounds may provide a valuable tool to elucidate D4R function and assess their potential as non-stimulant ADHD treatments. ObjectivesThis study examined the behavioral effects of two novel D4R drugs, namely, FMJ-01-38 (high-efficacy partial agonist) and FMJ-01-54 (full antagonist) in adolescent spontaneously hypertensive (SHR/NCrl) rats, a validated ADHD model, and Wistar controls. MethodsRats received intraperitoneal […]
- by Arnab, S., Fathi, P., Jones, E., Meyyappan, A., Nguyen, K. L., Bracchi-Ricard, V., Gupta, S., Fischer, R., Tom, V. J., Bethea, J. R.Chronic neuropathic pain (CNP) develops as a result of persistent neuroinflammation and maladaptive synaptic plasticity in the central nervous system following nerve injury. While tumor necrosis factor receptor 2 (TNFR2) signaling has been extensively studied in pain resolution, the expression of this receptor on specific neuronal populations and molecular pathways involved in spontaneous pain recovery still remains poorly defined. In this study, we investigated the role of TNFR2 signaling within hippocampal Nex/Neurod6+ pyramidal neurons in promoting recovery from chronic constriction […]
- by Gomez-Oliva, R., Chamorro-Francisco, A., Atienza-Navarro, I., Carrascal, L., Freire-Aragon, M. D., Hernandez-Galan, R., Nunez-Abades, P., Garcia-Alloza, M., Castro, C.Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine […]
- by Fuchs, N., El Gaamouch, F., Nada, H., Cho, S., Gabr, M.Fragment-based drug discovery (FBDD) remains a powerful tool in drug development for targeting a wide range of proteins and identifying new small molecule-based scaffolds. Here, we explored a fragment library of 3,200 compounds using a temperature-related intensity change (TRIC)-based high-throughput screening (HTS) approach, and successfully identified new scaffolds that bind to triggering receptor expressed on myeloid cells 2 (TREM2), a relevant target in neurodegenerative diseases and cancer immunotherapy. We first validated the hits with dose-dependent assays, then chose the three […]
- by ONANUGA, I. O., FOLARIN, R. O., Muniru, E. T., IBRAHIM, R. B., USMAN, I. M., JEGEDE, A. I., AZU, O. O., OBAYA, T. O., KEHINDE, M. O.Diabetic hyperglycemia is associated with severe complications, including neuropathy and cognitive impairment. This study examines the neuroprotective effects of Andrographis paniculata (AP) on the cerebrum cortex of alloxan-nicotinamide-induced diabetic male Wistar rats. Thirty-five male Wistar rats were randomly divided into five groups (A-E), each with seven rats. Diabetic hyperglycemia was induced via a single intraperitoneal injection of nicotinamide (110 mg/kg) followed by alloxan (120 mg/kg). Treatment included Andrographis paniculata, metformin and a combination of both. Untreated diabetic hyperglycemia resulted in […]
- by Uesono, Y.Various chemicals obey the Meyer-Overton correlation, in which potency increases exponentially with the partition coefficient. However, the principle remains unclear because of controversy between the lipid and protein theories. As the protein theory is based on the competitive inhibition of the non-membrane protein luciferase by alcohols and anesthetics, kinetic analysis was conducted on yeast hexose transporter Hxt2, a membrane protein. n-Alcohols (C2-C8) inhibited Hxt2 noncompetitively and drug efflux according to the correlation. Thus, the alcohols interacting nonspecifically with membrane affect […]
- by Capone, S., Paalangara, R., Gohin, S., Menard, A., Amy, C., Berrabah, W., Rogue, A., Getz, M. A., Alrubayyi, A., Battella, S., Raggioli, A., Gentile, M., Di Rita, A., Noto, A., Miselli, G., Grazioli, F., Napolitano, F., Sowcik, D., Soriani, M., Chmielewski, B., Molife, L., Muturi-Kioi, V., Makadzange, A. T., Gaiha, G. D., Ancian, P., Ackland, J., Folgori, A., Colloca, S.The rapid development of safe and efficacious vaccines is often hindered by extensive, mandated non-clinical safety evaluations in animals. Here we present the complete non-clinical studies for two investigational vaccines based on the GRAd platform, a gorilla-derived group C adenoviral vector. When administered intramuscularly, GRAd-COV2 and GRAdHIVNE1 were well tolerated. Studies in rats and rabbits showed localized distribution and transient, non-adverse inflammatory responses, while successfully inducing expected immune responses to their respective antigens. Notably, both vaccines demonstrated a consistent safety […]
- by Kämpfer, T., Ancarola, M. E., Zumstein, P., Bernal, A., Zumkehr, T., Mühlemann, S., Wiedemar, N., Lundström-Stadelmann, B.Succinate dehydrogenase (SDH, complex II), is essential for mitochondrial respiration. This study shows that triclabendazole and its primary metabolites inhibit SDH activity in mitochondria of the cestode Echinococcus multilocularis, while other tested benzimidazoles do not. Further analyses revealed that triclabendazole and metabolites also inhibit SDH in mitochondria of additional helminths (trematodes, nematodes) and mammalian cells. These findings indicate a shared mode of action and highlight potential safety risks associated with long-term triclabendazole treatment in mammals.
- Saxiphilin functions as a "toxin sponge" protein that counteracts the effects of saxitoxin poisoningby Nixon, S. A., Zakrzewska, S., Jang, S., Huang, K., Barra, A., Chen, Z., Goss, D. R., Park, E., Du Bois, J., Minor, D. L.Saxitoxin (STX) is among the most potent toxins known, is classified as a chemical weapon, and is the archetype of the paralytic shellfish toxin (PST) family produced by marine and freshwater harmful algal blooms (HAB)1-3. STX causes paralysis and death through inhibition of voltage-gated sodium channels (NaVs), has no antidote, and poses a public health and commercial fishing threat due to its accumulation in seafood and increasing HAB occurrences1,4. Although STX is lethal to varied vertebrates5-7, including humans4,8,9, certain frogs […]
- by Fiore, C. M., Rudokas, M., Masuda, R., Khamsopha, B., Sherpa, R. T., Moshal, K. S., Agarwal, S. R., Harvey, R. D.Sympathetic stimulation produces beneficial changes in cardiac function through {beta}-adrenergic receptor ({beta}AR) production of cAMP and subsequent alteration of electrical and mechanical activity. Long term activation of cAMP production also contributes to cardiac remodeling and detrimental changes associated with heart failure. However, sympathetic responses are mediated by the endogenous neurotransmitter norepinephrine (NE), which is also a potent 1-adrenergic receptor (1AR) agonist, and 1AR activation can produce significant effects on the heart as well. What is less clear is how 1- […]
- by Cao, Z., Zhou, C., Zhao, Q., Du, H.Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants known to induce developmental toxicity across multiple species, yet the molecular mechanisms are still not fully understood. This study aims to evaluate the developmental toxicity of four long-chain legacy PFAS (PFOA, PFOS, PFNA, PFDA) and one short-chain alternative (PFBA) at environmentally relevant concentrations (1-5 M) using the model organism Caenorhabditis elegans, with a focus on elucidating the underlying molecular mechanisms. Phenotypic analysis indicated that PFDA and PFOS significantly delayed development of […]
- by Leung, R., Wolf, E., Deme, J. C., Balakrishnan, S., Simoben, C. V., Feng, S., Macdonald, J. D., Chandrasekaran, R., Sun, J., Wang, X., Bolotokova, A., Zou, Y., Kannan, R., Ackloo, S., Wilson, D. J., Lea, S., Edwards, A., Arrowsmith, C., Peng, H., Halabelian, L., Schapira, M., Harding, R. J.Huntingtons disease (HD) is caused by a CAG repeat expansion mutation, giving rise to a polyglutamine expansion in the huntingtin (HTT). However, the explicit molecular functions of HTT and opportunities for direct pharmacological modulation remain incompletely understood. Here, we report the discovery of a small molecule ligand for the full-length HTT protein in complex with its partner, HAP40. Using affinity selection mass spectrometry (AS-MS), we identified a stereoselective binder, whose binding was characterized by surface plasmon resonance, hydrogen-deuterium exchange mass […]
- by Sahm, B. D. B., Florencio, K. G. D., Pinto, F. C. L., Maia, A. I. V., Rocha, C. A. M., Jimenez, P. C., Pessoa, O. D. L., Lotufo, T. M. C., Costa-Lotufo, L. V., Wilke, D. V.Marine holobionts are prolific sources of bioactive natural products. Previously, our group investigated cytotoxic compounds in zoantharians of the genus Palythoa and, herein, we further explored the anticancer potential of marine bacteria associated with P. variabilis. After isolating 10 culturable bacterial strains, we screened for cytotoxic activity on metastatic prostate tumor cells (PC-3/M) using the MTT assay. The crude extract of one of the strains (BRA-035), identified as Streptomyces sp., was selected due to its bioactivity profile and submitted to […]
- by Jabba, S. V., Erythropel, H. C., Anastas, P. T., Krishnan-Sarin, S., O'Malley, S., Zimmerman, J. B., Jordt, S. E.BackgroundSince late 2022, the sale of most flavoured tobacco products has been prohibited in California, including menthol cigarettes. Tobacco companies responded by introducing "non-menthol" cigarettes in which menthol was replaced with WS-3, an odorless synthetic cooling agent to elicit cooling sensations similar to menthol. Legislation enacted in 2024 banned the addition of cooling characterizing flavours in tobacco products in California. However, the industry continues to market "non-menthol" cigarettes in the state, with very similar package designs. It is unknown whether […]
- by Ojo, G. B., Olorunnisola, A. A., Adedayo, L. D., Morakinyo, A. O., Fakunle, R. R., Dawodu, E. S.This study investigated the antihypertensive effects of Allium sativum (garlic) on kidney function in a rat model of hypertension. Forty-eight Wistar rats were divided into groups: control, hypertensive, and hypertensive rats treated with different doses of garlic extract or a standard antihypertensive drug. Hypertension was induced by CaCl2 administration. The results demonstrated that garlic extract effectively lowered blood pressure in hypertensive rats, indicating its potential as an antihypertensive agent Further Analysis involve the histopathological examination of kidney tissues and analysis […]
- by Yang, X., Yu, B., Ma, J., Yan, Y., Wang, H., Dong, Q., Peng, S., Wu, Q., Zhang, T., Zhang, P., Jiang, Z., Lu, C., Li, L., You, X., Xu, Y., Joshua, B., Mu, Z., Zheng, M., Li, X., Hui, Q., Wang, X.Fibroblast growth factor 10 (FGF10) supports epithelial repair, but its role in liver fibrogenesis remains uncertain. Here we found that hepatic FGF10 and its receptor FGFR2 decline with progression to advanced fibrosis in patient biopsies and in carbon tetrachloride (CCl4)- and diet-induced mouse models. Restoring hepatic FGF10 with recombinant human FGF10 or adeno-associated virus mediated liver-targeted expression attenuated and partially reversed established advanced bridging fibrosis, reduced inflammation, and decreased hepatocyte apoptosis, and these benefits required hepatocyte FGFR2 because hepatocyte-specific Fgfr2 […]
- by Lumogdang, L. P., Guroalim, J. F. R., Domingo, P., Osabel, R.This study focused on determining the cytotoxicity of right-winged Musca domestica and assessing its bioactive compounds using FTIR spectroscopy. The cytotoxicity was evaluated using the Lc50 of the brine shrimp lethality assay. The Brine Shrimp Lethality Assay (BSLA) result shows that the extract obtained using the aqueous extract has the highest cytotoxicity. The FTIR analysis results showed different characteristic peaks and confirmed the presence of a functional group in the extract obtained using the aqueous extracts of Right-wing Musca domestica.
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