- by Graham, B., Nelson, T., Tavakoli, S., O'Dell, L., Addy, N. A., Bagdas, D.Chronic pain and nicotine use frequently co-occur, and individuals with chronic pain often experience greater difficulty quitting. Therefore, we examined nicotine withdrawal behaviors and analgesic-like effects in pain-naive and chronic pain conditions. Adult male and female rats underwent chronic constriction injury or sham surgery. After pain establishment, rats received twice-daily subcutaneous nicotine (0.3 or 0.7 mg/kg) or saline for 14 days. 24 h after the final injection, withdrawal was assessed, including physical signs and anxiety-like behavior. Depressive-like responses were evaluated […]
- by Dellavedova, J., Campera, C., Ancona, S., Rebecchi, M., Panzeri, V., Carzaniga, T., Casiraghi, L., Rocca, S., Di Ciolo, S., Pedretti, A., Tirelli, C., Buscaglia, M., Bellini, T., Romanelli, A., Villa, A., Brunialti, E., Borghi, E., Ciana, P.Exacerbations of respiratory viral infections significantly contribute to morbidity and healthcare burden. Among these viruses, Human Rhinoviruses (HRVs) are the most frequent causative agents of upper respiratory tract infections. To date, over 150 HRV serotypes have been identified, classified into three species: HRV-A, HRV-B, and HRV-C. No antiviral therapies are currently available against this viral family, largely due to the high serotype diversity and limited cross-protection. The major group of HRVs relies on the Intercellular Adhesion Molecule-1 (ICAM-1) receptor to […]
- by Yacoub, J., Bray, E., Bayyat, J., Glatfelter, G. C., Leake, A., Buitrago, E. M., Maitland, A. D., Partilla, J., Cavalco, N. G., Schalk, S. S., Lammers, J. C., Baumann, M. H., McCorvy, J., Leahy, J. W., Gulick, D., Witowski, C. G., von Salm, J. L.Serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) show therapeutic promise for psychiatric and neurodegenerative disorders but may be limited by liabilities from serotonin (5-HT)-2A mediated psychoactive effects and potential cardiotoxicity via 5-HT2B activation. To address these limitations, we designed and synthesized 2-halogenated derivatives of DMT and psilacetin to reduce 5-HT2A/5-HT2B activity while retaining engagement of therapeutically relevant targets, particularly 5-HT6, 5-HT2C, and 5-HT1B. This study demonstrated that 2-position halogenation decreased affinities, potencies, and efficacies at 5-HT2A and 5-HT1A […]
- by Nakaguma, Y., Kato, Y., Atef, Y., Ito, T., Nishimura, A., Uesugi, M., Kanda, Y., Kunisawa, J., Nishida, M.Vaccine adjuvants are critical for enhancing immune responses and sustaining antibody production. Although their safety profiles are well established, assessments have largely focused on metabolic and excretory organs such as the liver and kidneys, with limited attention to the heart. Here, we systematically evaluated the cardiac effects of five representative adjuvants in mice: alum, MF59, AS03, Sigma Adjuvant Systems, and lipid A. None of the adjuvants impaired baseline cardiac contractile function. Notably, lipid A uniquely enhanced mitochondrial respiratory capacity in […]
- by Palmer, M., Hashiguchi, T., Arman, A. C., Shirakata, Y., Buss, N. E., Lalezari, J. P.Background: Chemokine receptor type 5 (CCR5) is expressed on hepatic stellate cells (HSCs), which, together with fibroblasts, are major producers of extracellular matrix during liver fibrosis. Leronlimab is a humanized IgG4k; monoclonal antibody that binds to CCR5. The objective of the present study was to evaluate the antifibrotic effects of leronlimab in three independent preclinical studies using two mouse models of liver fibrosis. Methods: In STAM (Stelic Animal Model) model 1, leronlimab was administered at doses of 5 or 10 […]
- by Durnik, R., Juchelkova, T., Hecht, H., Winkelman, L. M. T., Beltman, J. B., Comoul, X., Jornod, F., Audouze, K., Blaha, L., Bajard, L.As toxicology shifts towards non-animal testing, quantitative models are essential to predict adverse health effects from molecular or cellular perturbations. Quantitative Adverse Outcome Pathways (qAOPs) represent such models, building on mechanistic knowledge and quantifying the Key Event Relationships (KERs) described in AOPs. Despite the recognized need, the number of qAOPs remains limited. Bayesian-based approaches are often chosen for developing qAOP for their flexibility, but most use discretized variables, limiting their predictive power. In addition, these models are mainly built from […]
- by Kuebler, I. R. K., Zimmerman, G., Ng, S. Q., Schneider, H. M., Sextro, K., Denning, A., Mattes, B., Matuszeski, M., Suarez, M., Wakabayashi, K. T.Sweetened alcoholic beverages are thought to contribute to developing Alcohol Use Disorder by increasing palatability. One monosaccharide, glucose, readily enters the brain more than fructose and directly impacts the activity of central neurons. The objective of this study is to determine the impact of glucose versus fructose on alcohol drinking patterns in female and male rats. Rats drank alcohol cocktails (1.25%-10%) containing either glucose or fructose (10%) in 4-hour sessions. We sought to parse orosensory effects from post-ingestive central effects […]
- by Arbelaez, N., Escobar-Chaves, E., Correa, A., Restrepo, A., Acin, S., Orozco, J., Balcazar, N.The acute, subacute, and subchronic oral toxicities, as well as the combined chronic toxicity and carcinogenicity, of a nanotechnology-based formulation derived from a natural extract of Eucalyptus tereticornis leaves were investigated. This nanoformulation demonstrates anti-obesogenic and potentially anti-diabetic properties. Our study aims to conduct preclinical tests to evaluate the chemical formulation. To assess acute toxicity, rats received a single oral dose of 2000 mg/kg of the nanoformulation. In the subacute trial, mice were treated with approximately 1180 mg/kg of the […]
- by Zhou, X., Youssef, Y., Miller, K. W.The neurosteroid allopregnanolone is a positive allosteric modulator of GABA(A) receptors, which has proved beneficial in the treatment of major depressive disorder and epilepsies. It also has a role in treating the mood swings that are associated with fluctuations in its level during the menstrual cycle. Nonetheless, a subset of women do not tolerate high levels of allopregnanolone. Iso-allopregnanolone, a negative allosteric modulator, as well as synthetic steroid antagonists are used to treat such conditions. However, steroid-based medications are difficult […]
- by Authement, A. K., Nath, A., Rubinow, K. B., Amory, J. K., Isoherranen, N.Cortisol is a major endogenous glucocorticoid that regulates numerous physiological processes. In plasma, cortisol and its inactive metabolite cortisone bind to corticosteroid-binding globulin (CBG) and albumin, leaving only the unbound fraction available for receptor activation and metabolism. Changes in ligand or protein concentrations alter unbound fractions. Existing binding equations are difficult to extend to multi-ligand, multi-protein systems and do not readily capture competitive endogenous binding interactions. The goal of this study was to develop a plasma protein binding model that […]
- by Liu, Y., Sun, W., Liu, J., Wu, H., Liu, P., Chen, Y., Zhang, R., Chen, W., Wang, S., Guo, X., Zhang, W., Cao, L.BackgroundIt has been shown that n-3 polyunsaturated fatty acids (n-3 PUFA) of marine origin exert significant beneficial effects on myocardial infarction (MI); however, the underlying mechanisms remained unclear. Ceramides play a vital role in the regulation of energy metabolism, mitochondrial function, and apoptosis. Through the integration of clincial studies and animal experiments, this study aimed to determine whether n-3 PUFA improved myocardial function by modulating ceramide metabolism. MethodsIn a case-control study, 100 patients with AMI and 100 healthy pariticipants were […]
- by Clayton, J., Kozell, L. B., Eshleman, A. J., Bloom, S. H., Schutzer, W. E., Abbas, A. I., Stavitskaya, L., Shen, J.Nitazenes are driving a wave of overdose deaths in the United States and Europe and often require additional doses of naloxone to reverse. To understand the molecular basis, we conducted a joint experimental and simulation study of three common nitazenes, eto-, etodes-, and protonitazene. Radioligand experiments demonstrated that all three nitazenes display higher receptor affinity and longer dissociation half-lives than fentanyl. Notably, protonitazene dissociates slower than carfentanil and its displacement requires fourfold higher antagonist concentrations. The observed trend in nitazene […]
- by Gleneadie, H. J., Francis, T., Mo, S. P. L., Ahmed, A., Bensalah, M., Muntoni, F., Harridge, S. D. R., Merkenschlager, M., Fisher, A. G.BackgroundThe X-linked muscle wasting disorder Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal disease caused by loss of function mutations in the dystrophin (DMD) gene. Upregulation of utrophin (UTRN), an embryonic homologue of dystrophin, has been proposed as a therapeutic option that could ameliorate disease. We previously generated a bioluminescent screen for utrophin-upregulating compounds using a mouse reporter of endogenous utrophin expression and discovered that inhibition of ERK1/2 and EZH2, increases utrophin expression in myoblasts. MethodologyHere we extend […]
- by Lozano, L. P., Boyce, T. M., Groves, A. P., Keen, H. L., Boldt, H. C., Mullins, R. F., Binkley, E. M., Tucker, B. A.PurposeCompare the effect of MEK inhibition on iPSC-derived retinal pigmental epithelial (RPE) cells generated from a patient who developed MEK inhibitor-Associated Retinopathy (MEKAR) versus a patient who did not develop retinopathy. DesignCase-control SubjectsTwo female patients with Neurofibromatosis Type 1 who were treated with MEK inhibitors. One patient developed MEKAR, the other did not. MethodsRPE were generated from human induced pluripotent stem cells (hiPSCs) from these two patients. These hiPSC-derived RPE were treated with selumetinib for 10 days. Main Outcome MeasuresPhagocytic […]
- by Besztercei, B., Antal, R., Tahtivaara, L., Lappetelainen, B., Jaaskelainen, N., Szappanos, A., Lukats, A., Pal-Kajtar, A., Budai, A., Cerrada-Gimenez, M., Kovacs, K. A.Pathological neovascularization in the eye is a significant contributor to vision loss in diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. While anti-VEGF biologics are effective, they require repeated intravitreal injections and carry procedural risks. Here, we report a novel principle for designing photoactivatable VEGFR2 inhibitors, along with two examples, EYE1090 and EYE1118, engineered from the sunitinib and vorolanib scaffolds, respectively. Azido-functionalization in these molecules enables light-triggered receptor binding while preserving potent inhibition in the dark. Both compounds […]
- by Marshall, D. A., Litwa, K. A., Soderstrom, K.The non-euphorigenic phytocannabinoid cannabidiol (CBD) has demonstrated therapeutic efficacy in childhood-onset epilepsies. Using a songbird preclinical model we have found that CBD promotes recovery of learned vocalizations following focal motor cortical injury. But questions about cellular mechanisms supporting this protection remained. Songbird vocal learning, like human speech, depends on development and maintenance of specialized neural circuits. Partial lesioning (microlesions) of the vocal pre-motor cortical-like song region HVC transiently disrupts song structure and triggers injury-associated cellular stress responses across interconnected song […]
- by Lu, D., Yu, X., Wang, J.Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of programmed cell death and is implicated in various pathological conditions, particularly in mediating tumor resistance to immune checkpoint inhibitors (ICBs). In this study, we have pioneered the development of a novel cereblon (CRBN)-recruiting RIPK1 degrader, LD5095, through systematic optimization of linker and CRBN ligand portion. LD5095 demonstrates potent and selective RIPK1 degradation across cell lines, with rapid kinetics and sustained degradation over 72h post-washout. Functionally, RIPK1 degradation by LD5095 significantly […]
- by Kuncewicz, K., Upadhyay, S., Ge, Y., Duan, H., Gabr, M.CD28 co-stimulatory blockade is an established therapeutic strategy in autoimmune disease, yet every clinical-stage agent shares a structural limitation: high-affinity, long-lived receptor occupancy that precludes dynamic control of immune suppression. In chronic inflammatory conditions, where prolonged immunosuppression carries infection risk and necessitates treatment interruptions, no existing agent permits rapid restoration of immune function. We report CP8, a disulfide-constrained cyclic peptide antagonist that matches the inhibitory potency of clinical-stage CD28 biologics (FR104, Acazicolcept, and Lulizumab) across primary human immune cells from […]
- by Mazzola, J. M., Rosenfeld, M., Tucker, M., Wezeman, J., Ladiges, W. C., Liao, G. Y.Age-related cognitive decline (ARCD) is driven by conserved biological mechanisms of aging, yet no gerotherapeutic directly targets these processes in the brain. Glycyl-L-histidyl-L-lysine complexed with copper (GHK-Cu) is an endogenous peptide with regenerative and anti-inflammatory properties that declines with age. Whether its effects on cognitive aging depend on delivery route or exposure duration remains unclear. Aged C57BL/6J mice (20-21 months) received GHK-Cu (15 mg/kg) via short-term intraperitoneal (IP; 5 days) or longer-term intranasal (IN; 8 weeks) administration. Hippocampal-dependent escape learning […]
- by Kemzeu, R., Tchokouaha Yamthe, L. R., Njanpa Ngansop, C. A., Madiesse Kemgne, E. A., Pone Kamdem, B., Ngouana, V., Ngoutane Mfopa, A., Donbou Djiotie, C. P., Tsouh Fokou, P. V., Tsakem Nangap, J. M., Lunga, P. K., Bruno, L. N., Fekam Boyom, F.The urgent need for new antileishmanial drugs with novel mechanisms of action is driven by the limited efficacy, high toxicity, and growing resistance to currently available treatments. This study investigates the antileishmanial potential of extracts from Pinus sp., a plant widely used in the Cameroonian pharmacopoeia to treat various infections, including cough and fever conditions. The antileishmanial activity of the ethanol, methanol, hydro-ethanol, and hydro-methanol extracts of Pinus sp. leaves were evaluated against Leishmania donovani promastigotes and amastigotes using a […]
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