- by Berthome, Y., Le Coz, G.-M., Utard, V., Gu, Q., Fellmann-Clauss, R., Petit-Demouliere, N., Quillet, R., Gaveriaux-Ruff, C., Ramanoudjame, S., Esteoulle, L., Humbert, N., Daubeuf, F., Gizzi, P., Riche, S., Leroy, X., Bonnet, D., Simonin, F.Chronic pain affects a significant portion of the global population and imposes substantial clinical and socioeconomic burdens. Current treatments mainly rely on opioid analgesics, which carry serious risks of dependence and misuse, underscoring the urgent need for alternative therapeutic strategies. Galanin receptors (GALR1-3) are known to be involved in modulating pain, yet their specific roles remain poorly understood due to the lack of receptor subtype-selective ligands. Recently, spexin has been identified as an endogenous peptide that selectively activates GALR2 and […]
- by Mali, K., Zhang, D., Bazina, L., Abramova, E., Zhang, J., Zhan, T., Pattarawat, P., Moularas, K., Zhang, Q., Gaskins, A. J., Gow, A., Demokritou, P., Xiao, S.Wildfires have become more frequent and intense worldwide. Wildfire emitted particulate matter (WFPM) can be more toxic than urban background PM due to its greater content of nanoscale size (WFPM0.1) and presence of more polar organic compounds including polycyclic aromatic hydrocarbons (PAHs). While exposure to WFPM has been linked to cardiovascular and respiratory diseases, its impact on female reproduction remains elusive. Here, we used an in vivo mouse intratracheal exposure model and a 3D ovarian follicle culture system, together with […]
- by Rives, C., Poirier-Jaouen, N., Martin, C. M. P., Huillet, M., Ellero-Simatos, S., Perrier, P., Polizzi, A., Lasserre, F., Alquier-Bacquie, V., Guyon, C., Lippi, Y., Naylies, C., Jasmin, E. L., Dieng, N.-K., Vuillaume, R., Orlandi, C., Gomez, J., Costes, S., Arrar, A., Lucas, A., Fried, S., Boutet-Robinet, E., Guillermet-Guibert, J., Kesse-Guyot, E., Guillou, H., Loiseau, N., Fougerat, A., Payrastre, L. G.Chronic exposure to pesticide mixtures through diet is common, yet their combined metabolic effects and interactions with dietary factors remain unclear. We identified four pesticides prevalent in human exposure (imazalil, thiabendazole, boscalid, lambda-cyhalothrin) and assessed their combined impacts on hepatic metabolism and metabolic homeostasis using human liver cells and male mice fed standard chow or western diets. We found that the pesticide mixture induced metabolic perturbations in human hepatocytes. In addition, the pesticide mixture altered hepatic gene expression in chow-fed […]
- by Ye, X., Hu, H., He, Y., Ye, F., Jin, J., Gaucher, J.-F., Wang, L., Broussy, S.Gastric cancer is among the most common cancers and represents a major public health problem worldwide. New therapeutic strategies and drugs are needed. Anti-angiogenic agents targeting the Vascular Endothelial Growth Factor (VEGF) are used in combination therapy in the clinic, although their efficacy remains modest. We believe that these large anti-VEGF antibodies could be advantageously replaced by smaller peptides with better tissue penetration. In this study, we evaluate the efficacy of a previously described dimer peptide ligand of VEGF, D6, […]
- by Decosterd, L. A., Briki, M., Wagner, C., Desfontaine, V., Vocat, A., Opota, O., Abou-Zite, S., Corpataux, O., Cena, B., Guinchard, S., Versace, F., Murisier, A., Mercier, T., Blattes, E., Bardinet, C., Thoueille, P., Wsol, V., Chtioui, H., Rothuizen, L., Nahimana, A., Bellotti, A., Chiarelli, L. R., Spaggiari, D., Dhar, N., Mishra, R., Sommer, R., Lupien, A., Duchosal, M. R., Guery, B., Girardin, F., Milano, G., Ryabova, O., Makarov, V., Buclin, T., Cole, S. T., Choong, E.Macozinone (MCZ, PBTZ169) is a potent clinical stage benzothiazinone antitubercular agent that covalently inhibits the essential mycobacterial flavoenzyme DprE1. In some mammals, MCZ undergoes reductive dearomatization to H2MCZ, a Hydride Meisenheimer Complex, identified as the major circulating metabolite in humans. We demonstrate for the first time that the NADPH-dependent human prostaglandin reductases PTGR1 and PTGR2 catalyze MCZ dearomatization into H2MCZ, resulting in loss of antimycobacterial activity. This reaction represents a heretofore undescribed host-mediated metabolic inactivation pathway for a therapeutic agent. […]
- by Meganathan, D. P., Banzon, R., Casanova, A., Sarikhani, E., Mahato, K., Vu, H., Reade, S., Ambika Devarajan, I., Tahir, A., Sasi, L., Spain, L., Wang, J., Jahed, Z.Potassium ion (K) dynamics are central to cardiac electrophysiology, with early disruptions in K flux often preceding arrhythmia and contractile dysfunction. However, current sensing technologies, such as patch-clamp, Microelectrode arrays (MEAs), and fluorescent indicators, either lack chemical specificity for K or are unsuitable for long-term, single-cell analysis. Conventional ion-selective electrodes (ISEs), while more selective, are limited by bulk phase design and poor spatial resolution. To address these limitations, we present KINESIS (K Ion Nano-Electrode Selective Interface System), a nanofabricated, cell-compliant […]
- by Adachi, Y., Sugimoto, M., Yamada, Y., Kanda, J., Yonezawa, A., Yamagiwa, T., Hanyu, Y., Watanabe, M., Arai, Y., Mizumoto, C., Kitawaki, T., Kondo, T., Yamashita, K., Imayoshi, N., Shigetsura, Y., Katsube, Y., Ikuta, K., Hira, D., Ikeda, R., Takaori-Kondo, A., Nakagawa, S., Terada, T.Background Patients undergoing hematopoietic stem cell transplantation (HSCT) often receive multiple antibiotics and antifungal agents concurrently, making it crucial to understand potential pharmacokinetic interactions. We report here an interaction between the glycopeptide antibiotic teicoplanin (TEIC) and sulfo-butyl ether-beta-cyclodextrin (SBECD), a solubilizing excipient in the intravenous formulation of posaconazole (PSCZ). Methods We performed a single-center retrospective analysis of HSCT patients who received oral and intravenous PSCZ during TEIC therapy. Associations between PSCZ administration and TEIC concentration-to-dose (C/D) ratios were evaluated using […]
- by Manousopoulou, A., White, C. H., Hamal, S., Nihalani, R., Budoff, M. J., Garbis, S. D.BACKGROUND: As a GLP1 R agonist, semaglutide is known to exhibits pleiotropic health effects across the cardiometabolic spectrum in patients with type 2 Diabetes Mellitus (T2D). However, in depth and unbiased protein and phosphoprotein level evidence that reflects such effects of semaglutide in plasma remains elusive. OBJECTIVES: This pilot study applied an innovative plasma proteomics and phosphoproteomics technology to a sub-set of patients with T2D that participated in the Semaglutide Treatment effect on coronary atherosclerosis Progression (STOP) randomized trial. The […]
- by Enwere, M., Turiello, R., Foo, J., Nouwairi, R., McElroy, J. H., Medearis, E., Smith, D., Laurell, N., Clayton, A., Yarlagadda, A., Aitchison, K., Venton, B. J., Landers, J. P.Specific drug metabolism rates are defined by the constituency of the cytochrome P450 (CYP) genome, including polymorphic changes in any of 200+ CYP genes. An example is CYP2C19, where associations of gene polymorphisms with variability in certain drug metabolism rates have been linked to inter-individual and inter-ethnic differences in therapeutic outcomes. While pharmacogenomic screening for these variants prior to drug and dosage prescription has well-defined links to better treatment outcomes, current implementation is limited to complex and costly variant-probing and […]
- by Deng, Y., Bass-Stringer, S., Bond, S., Cross, J., Truong, J., Hugen, L., Woo, H.-Y., Rosdah, A., Kong, A., Hart, C., Gorringe, K. L., Ritchie, R., Sanij, E., Drew, B. G., Greening, D., Ngo, D., Lees, J., Holien, J., Lim, S. Y.BackgroundAnthracyclines such as doxorubicin are effective chemotherapeutics but are limited by cardiotoxicity driven in part by mitochondrial dysfunction. Dysregulated mitochondrial dynamics, particularly excessive dynamin-related protein-1 (Drp1)-mediated fission, contribute to doxorubicin-induced cardiac injury and support selective survival of cancer cells. ObjectivesTo determine whether DRP1i2, a novel small molecule Drp1 inhibitor targeting a conserved domain shared between human and mouse, can function as a cardio-oncology therapeutic by reducing doxorubicin-induced cardiotoxicity while maintaining or enhancing anti-cancer efficacy. MethodsCardioprotective effects of DRP1i2 were evaluated […]
- by K, S., Jadhav, P., Mehaboob, S., Shahapur, S., Kadiyala, G., Saxena, U.Hypertriglyceridemia is a dominant and early metabolic abnormality underlying fatty liver disease in Indian populations, often preceding obesity, insulin resistance, or inflammatory liver injury. Many diet-induced rodent models of hepatic steatosis rely on extreme obesogenic or fructose-rich diets that poorly reflect real-world Indian dietary patterns. Here, we describe a diet-induced rat screening model designed to reflect typical Indian cereal-rich, visible-fat dietary exposure and to preferentially induce triglyceride-centric hepatic lipid accumulation. The model reproducibly induces hepatic triglyceride deposition with preserved liver […]
- by Baues, M., Elgokha, A., Nguyen, M. M. H., Schwering-Sohnrey, M., Ko, T., Schwermer, F., Perri, F., Opitz, T., Kelly, T., Huberfeld, G., Borger, V., Schneider, M., Surges, R., Beck, H., Trauner, D., Mueller, C. E., Wenzel, M.Photo-activatable drugs (PDs) are rapidly emerging as precision therapeutics across biomedical research, yet their potential in epilepsy treatment has remained understudied. Given that 30% of epilepsies are medically refractory, and anti-seizure medications often cause multi-organ side-effects, PDs could break new ground. Here, we evaluate light-switchable ion-channel blockers QAQ and CQAQ, and a newly developed caged propofol (CaP), in murine brain slices, and postsurgical brain tissue from patients with epilepsy or brain tumors. In mice, we show that QAQ/CQAQ reversibly suppress […]
- by Sagar, S. C., Tapadia, M. G.BackgroundPolycystic kidney disease (PKD) is a genetic disorder characterized by progressive cyst formation, epithelial disorganization, and impaired fluid transport, ultimately leading to renal failure. Disruption of cytoskeletal dynamics and epithelial polarity is central to PKD pathogenesis. Malpighian tubules (MTs) of Drosophila melanogaster serve as a conserved renal analog, and caspase-3/Drice-deficient flies exhibit a robust PKD-like tubular phenotype, providing a powerful in vivo model to investigate therapeutic interventions. PurposeThis study evaluates the therapeutic potential of the Brahmi Ghrita (BG) in ameliorating […]
- by Chittimalli, K., Rozario, H. E., Martinez, V., McAdams, Z. L., Adkins, S. A., Ericsson, A. C., Jarajapu, Y. P.Aging is associated with colon epithelial barrier integrity and upregulation of myelopoiesis in the bone marrow (BM). Alamandine (Ala) and MrgD are novel members of the renin angiotensin system (RAS). This study tested the hypothesis that Ala restores the colon epithelial barrier integrity in aging via modulating gut-BM axis. Mice of age 2-3 (Young) or 22-24 months (Old) were treated with saline or Ala by using Osmotic pumps. The intestinal permeability was evaluated by using FITC-dextran. Lgr5+Olfm4+ intestinal stem cells […]
- by Hong, C. R., Dickson, B. D., Liew, L. P., Wong, W. W., Jaiswal, J. K., Jamieson, S. M. F., Ross, J. M., Zhong, L., Shackleford, D. M., Wilson, W. R., Hay, M. P.Hypoxic tumour cells are resistant to many forms of cancer therapy, particularly radiotherapy. Hypoxia-activated prodrugs (HAPs) can potentially address this problem through selective release of drugs ( effectors) in oxygen-deficient microenvironments, via metabolic reduction of a nitro(hetero)aromatic trigger moiety. While many such HAPs show marked selectivity for hypoxia in cell culture, none have yet been approved for clinical use. Here, we report HAPs that release a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK) which, like hypoxia, […]
- by Sun, Q., He, G., Bartuzi, D., Silva, A. G., Kedzierska, E., Stepnicki, P., Adamus, A., Targowska-Duda, K. M., Wrobel, T. M., Castro, M., Carlsson, J., Liu, X., Kaczor, A. A.Progress in understanding protein-ligand interactions is revolutionizing drug design, especially for G protein-coupled receptors (GPCRs), which are targets for 35% of marketed drugs.1 The dopamine D2 receptor (D2R) represents a key drug target in schizophrenia and Parkinsons disease.2 While structural studies have clarified its interactions with classical ligands, the behavior of atypical, non-basic ligands like D2AAK2 remains unclear. Notably, D2AAK2 shows strong selectivity for D2R over the closely related D3R, despite identical binding pocket composition. Here, we present a cryo-EM […]
- by Chalkiadaki, M., Grigoraki, L., Tsakireli, D., Vasalaki, G., Tzimas, P. S., Chen, M., Remadi, L., Ragno, R., Akrani, I., Mikros, E., Panteleri, R., Vlogiannitis, S., Myrianthopoulos, V., Kostakis, I. K., Skaltsounis, L. A., Vontas, J., Halabalaki, M.Insecticide resistance in mosquitoes, largely mediated by cytochrome P450 monooxygenases (CYPs), compromises the efficacy of vector control tools. In this study, chemically-wise selected natural extracts and compounds were screened for their CYP inhibition potential. Among 37 tested plant extracts and fractions, a decarboxylated acidic fraction of industrial hemp (Cannabis sativa Linnaeus var. Futura 75) emerged as a promising hit, and phytochemical profiling identified cannabidiol (CBD) as its major component (IC = 18.37 M for CYP9K1). CBD was used as a […]
- by Grandclaudon, M., Boulch, M., Thaller, A., Sabio-Ortiz, J., Grimaldi, A., Goxe, M., Knopf, A., Daugan, M. V., Huehn, E., Gnerre, C., Jeay, S., Faronato, M., Dakhli, H., Lopez-Lastra, S., Hardy, A., Sanchez, S., Mayer, I., Hoste, R., Montanari, F., Soumelis, V., Alberti, J., Pattarini, L., Hoffmann, C., Pierce, A. J.Immune checkpoint inhibitors, particularly T cell targeting anti-PD(L)1 therapies, have revolutionized the treatment landscape for solid malignancies, but challenges related to non-responsiveness and the development of treatment resistance continue to be observed. An additional immunosuppressive axis relates to prostaglandin signaling downstream of cyclooxygenase-2 (COX2), where COX2 inhibitors have shown clinical promise in re-engaging both T and non-T cell immune compartments, yet have suffered from toxicity concerns. We report here the preclinical characterization of OKN4395, a highly potent and specific first-in-class […]
- by Smoot, S. R., Tourigny, J. P., Holsopple-Bowen, J. M., Fitt, A. J., Pena-Garcia, Y., Lowe, M. R., Rose, D. A., Zolman, N. C., Thrasher, G. H., Arya, S. S., Vires, H. B., Adams, E. C., Colbourne, J. K., Shaw, J. R., Oliver, B., Nemkov, T., D'Alessandro, A., Kaufman, T. C., Tennessen, J. M.Arsenic exposure is a pervasive global health threat strongly associated with increased risk of morbidities such as diabetes, cardiovascular disease, and cancer. Despite extensive studies describing the dangers of arsenic exposure, the molecular initiating events that link arsenic to chronic disease onset and progression remain poorly defined. To address this knowledge gap, we combined time-resolved transcriptomic and metabolomic profiling of adult Drosophila melanogaster exposed to sodium (meta) arsenite (NaAsO2). We uncovered coordinated, dose-dependent shifts in gene expression and metabolite abundance […]
- by Preza, M., Dietrich, N., Zumstein, P., Steinmann, J., Hiller, L., Zumkehr, T., Kämpfer, T., Chollet-Krugler, M., Vetter, L., Hemphill, A., Dion, S., Lundström-Stadelmann, B.BackgroundEchinococcosis is a zoonotic disease caused by cestodes of the genus Echinococcus. Alveolar echinococcosis (AE), caused by E. multilocularis, primarily affects the liver and shows infiltrative, tumor-like growth of the metacestode stage. If untreated, AE is lethal. AE remains a neglected disease with current treatments based on albendazole or mebendazole that are parasitostatic, and not curative, underscoring the need for more effective therapies. Niclosamide is a chlorinated salicylanilide derivative with proven activities against intestinal helminths but is inactive against tissue-dwelling […]
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