- by Mantuano, P., Mele, A., Boccanegra, B., Tanganyika-de Winter, C., Van De Vijver, D., Schneider, A.-F., Mele, M., Cappellari, O., Tulimiero, L., Engelbeen, S., Suidgeest, E., van der Weerd, L., Aartsma-Rus, A., De Luca, A., Gordish-Dressman, H., van Putten, M.Introduction. The quality of preclinical studies for rare diseases, such as Duchenne muscular dystrophy (DMD), relies on the availability of comprehensive natural disease history data. In addition to the classic BL10-mdx mouse, in recent years, the D2-mdx model has increasingly been used as an alternative model due to its reportedly more severely impaired phenotype. To improve our understanding of disease progression in these two DMD models, we conducted a comprehensive natural history study. Materials and Methods. This involved a cross-sectional […]
- by Aryeh, K. S., Tsang, Y. P., Hsu, E. W., Yeung, C. K., MacDonald, J., Bammler, T. K., Himmelfarb, J., Rehaume, L. M., Kelly, E. J.Abstract Background: Calcineurin inhibitors (CNIs) are indispensable for transplantation immunosuppression, yet cyclosporine A (CsA) produces renal toxicity. Voclosporin (VCS), a CsA analog, is proposed to be less nephrotoxic, but mechanisms remain unclear. Methods: Primary human proximal tubule epithelial cells (PTECs) were exposed to CsA or VCS in 2D monolayers and perfused 3D kidney microphysiological system (MPS). Viability was assessed in 2D cultures by MTS, mitochondrial membrane potential ({Delta}{Psi}m) by TMRM flow cytometry, and soluble injury and inflammatory biomarkers in MPS […]
- by Ferguson, S., Mesnage, R., Antoniou, M.Evidence of negative health and environmental effects of glyphosate-based herbicides (GBHs) has led to marketing of glyphosate-free formulations. A frequent glyphosate replacement is pelargonic acid, which is rapidly degraded, leading to claims of greater safety and less environmentally damaging than GBHs. However, toxicity of commercial pelargonic acid formulations containing several co-formulants have not been determined. Using Roundup NL, a representative pelargonic acid-based herbicide, we undertook tissue culture cell assays measuring viability, plasma membrane integrity, DNA damage, and activation of stress-response […]
- by Grgic, D., Jobst, M., Pais, M., Waesoh, N., Hager, S., Del Favero, G., Marko, D.Tenuazonic acid (TeA) is an emerging Alternaria mycotoxin frequently detected in food and feed commodities, raising concerns about its toxicological relevance. Chronic oral exposure to TeA has been reported to induce dysplastic alterations in the esophageal mucosa of mice, while human biomonitoring data indicate an association between TeA exposure and esophageal cancer, although a causal relationship has not yet been established. At a mechanistic level, the effects of TeA in esophageal cells remain poorly characterized. Therefore, this study investigated the […]
- by Partsch, V., Crudo, F., Schröeder, C., Del Favero, G., Marko, D.Alternaria fungi produce various structurally diverse mycotoxins, several of which exhibit immunomodulatory properties. Among these, alternariol monomethyl ether (AME), alternariol (AOH), alterperylenol (ALTP), altertoxin I (ATX-I), and altersetin (AST) have been reported to suppress lipopolysaccharide (LPS)-induced inflammatory responses. However, the precise molecular mechanisms underlying these effects remain unclear. The present study aimed to elucidate how these selected Alternaria mycotoxins (0.1-50 M) target the NF-{kappa}B signaling pathway in THP-1 monocytes. Key components of the NF-{kappa}B cascade were analyzed by immunofluorescence microscopy, […]
- by Kalaniopio, P. H., Gibbons, L. B., Allen, R. S., Matthews, S. M., Lujan, O. R., Gaaloul, E., Wilbanks, J., Allen, C. M., Chassman, C. A., Traustadottir, T., Propper, C. R., Salanga, M. C.Depleted uranium (DU) is an environmental contaminant with a 30 {micro}g/L (ppb; parts per billion) EPA maximum contaminant level (MCL) for drinking water. The mining of uranium and use of DU in modern weapons underly human exposure that disproportionally impacts military and tribal communities in the United States. Uraniums radiotoxic characteristics are understood, but its chemical hazards much less so. In zebrafish (Danio rerio) and human cell cultures we test the hypothesis that exposure to DU negatively impacts cellular function […]
- by Wilson, B., Johnson, L., Liu, J., Caggiano, N., Subraveti, N., Nagapudi, K., Tsourkas, A., Prud'homme, R., Ristroph, K.Extrahepatic delivery of lipid nanoparticles (LNPs) to non-phagocytic cells is a major challenge, with the leading strategy involving surface functionalization with target-specific monoclonal antibody (mAb) ligands. We investigate the stability of mAb-conjugated LNPs using two anchoring systems: the commonly used DSPE-PEG2kDa-maleimide and a block copolymer, PCL5kDa-b-PEG2kDa -maleimide, with the hypothesis that conjugation to a 150,000 Da antibody could overwhelm the relatively small [~]600 Da aliphatic anchor on the PEG-lipid in vivo. Shedding of the mAB would compromise targeting. Conjugation integrity […]
- by Fomesseng Negoue, A., Eya'ane Meva, F., Fokou, J. B. H., Voundi Olugu, S. H., Boudjeka, V., Ngo Nyobe, J. C., Belle Ebanda Kedi, P., Houatchaing Kouemegne, A. M., Etame Loe, G.BackgroundNatural essential oils exhibit antimicrobial and wound-healing properties, but their therapeutic application is limited by poor water solubility, volatility, and instability. This study developed and characterized a nanoemulsion of Ocimum gratissimum essential oil (OGNe) and evaluated its physicochemical properties, dermal safety, antibacterial activity, and wound-healing potential. MethodsEssential oil was obtained by hydrodistillation and formulated into nanoemulsions by high-speed stirring emulsification. Physicochemical properties, including pH, droplet size, polydispersity index, and storage stability, were determined. Acute dermal toxicity was assessed in Wistar […]
- by Eya'ane Meva, F., Gouli Lougui, L. P., Nguemfo, E. L., Fannang, S. v., Ntoumba, A. A., Bamal, H.-D., Beglau, T. H. Y., Tako Djimefo, A. K., Mintang Fongang, U. A., Sone Enone, B., Tchangou Njiemou, A. F., Evouna, D. I. M., Yinyang, J., Chimi Tchatchouang, G., Fonye Nyuyfoni, G., Janiak, C.IntroductionThromboinflammation, which represents the pathological interplay between inflammation and thrombosis, is a leading cause of global mortality. Current therapies are frequently associated with an increased risk of bleeding and do not adequately address the inflammatory component of the disease. The African tree Guibourtia tessmannii represents a promising source of natural anti-inflammatory compounds. This study aimed to synthesize and characterize silver nanoparticles using an aqueous bark extract of G. tessmannii (GT-AgNPs) and to evaluate their anti-inflammatory and anticoagulant properties. MethodsGT-AgNPs were […]
- by Elias, K. A., Brown, S. D., Feigh, M. F., McDonnell, N. D., Plonowski, A.Background & AimsActivation of apoptosis signal-regulating kinase 1 (ASK1), a ubiquitous redox-sensitive kinase, results in inflammation, apoptosis, and fibrosis, key common pathways in human liver disease. SRT-015 is a novel, small molecule inhibitor of ASK1. This study evaluated the in vitro efficacy of SRT-015, compared it to other ASK1 inhibitors, and determined the in vivo efficacy of SRT-015 across multiple acute and chronic liver disease models. MethodsIn vitro studies determined the kinase potency and selectivity of SRT-015, and cellular studies […]
- by Mirando, A. C., Lima e Silva, R., Shen, J., Robinson, T. J., Green, J. J., Campochiaro, P. A., Popel, A. S., Pandey, N. B.Retinal and choroidal vascular diseases are major causes of vision loss that require frequent intravitreal anti-VEGF therapy. Anti-angiogenic peptide AXT107 demonstrated efficacy in preclinical studies and was advanced to the clinical stage. To provide for sustained delivery of the peptide and avoid complications with intravitreal injection, we evaluated suprachoroidal delivery of AXT107 microparticles (MP-AXT107). The original, soluble AXT107 formulation was ineffective at inhibiting laser-induced choroidal neovascularization (CNV) in our rat model and was consequently reformulated as microparticles. MP-AXT107 demonstrated high […]
- by Sanchez-Guerrero, G., Umbaugh, D., Nguyen, N., Jaeschke, H., Ramachandran, A.An acetaminophen (APAP) overdose is the leading cause of drug-induced hepatotoxicity and acute liver failure (ALF) in the United States. While N-acetylcysteine (NAC), is highly effective when administered early after an overdose, its efficacy decreases with delayed administration. Since most patients present late to the clinic, there is an urgent need for novel late-acting therapeutic options to prevent progression to ALF. We previously demonstrated the benefit of delayed activation of the Adenosine A2B Receptor (A2BAR) in attenuating APAP-induced hepatotoxicity and […]
- by Williams, P. D. E., Borts, D. J., Liu, D., Byerley-Duke, J., VanVeller, B., Martin, R. J.Anthelmintic drugs are used to control soil-transmitted helminths that infect a third of the worlds human population. There is increasing concern about the development of resistance to anthelmintic drugs because of the limited number of compounds available and there is an unmet need for new resistance-busting drugs. Here we describe the presence of a previously unrecognized endogenous acetylcholine analogue, {beta}-alanine betaine, which may serve as an endogenous ligand for an alternate subfamily of nicotinic receptors (DEG-3/DES-2) that could be developed […]
- by Boyle, S., Schaack, S.High concentrations of steroidal hormone compounds are a growing source of concern for environmental pollution in aquatic ecosystems. In this study, we examine the effects of two estrogenic compounds (estriol and 17-ethinylestradiol) on fitness traits in the aquatic microcrustacean, Daphnia magna, a key bioindicator species for toxicology studies. The impacts were compared of two forms representing a natural and synthetic estrogenic compound. Growth and reproduction traits were assayed by exposing Daphnia to each estrogen type at four concentrations reflecting potential […]
- by Hoshino, J., Irie, K., Konishi, A., Akiyama, H., Minamishima, Y. A.Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are widely used for the treatment of renal anemia; however, their effects on intraocular vascular endothelial growth factor (VEGF) expression remain unclear. In this study, we examined the effects of all five HIF-PH inhibitors –roxadustat, daprodustat, vadadustat, enarodustat, and molidustat–on Vegfa expression in the retina in mice. C57BL/6J mice were orally administered each inhibitor. Six hours after administration, the kidney, retina, and liver were collected, and transcription levels were quantified by real-time quantitative reverse […]
- by Weaver, E. M., Topletz-Erickson, A., Isoherranen, N., Unadkat, J. D., Arnold, S. L. M.BackgroundThe placenta serves a critical role in nutrient uptake and waste elimination for the developing fetus. The placenta is also responsible for the uptake and/or exchange of xenobiotics, including medications, between the maternal and fetal bloodstreams. An estimated 40-80% of women take medications or drugs during pregnancy for a variety of conditions. Very little is understood about fetal drug and nutrient exposure during pregnancy and how it may change over the course of fetal development. ObjectiveThis study aimed to characterize […]
- by Li, Q., Pfersdorf, F., Salgado-Polo, F., Gustavsson, M.Chemokines orchestrate immune cell trafficking through receptor-mediated signaling and are implicated in inflammatory, autoimmune, and neuropathic disorders. The XCL1-XCR1 axis is of particular interest because XCR1 is selectively expressed on mature conventional type 1 dendritic cells (cDC1s), where it supports communication with activated CD8+ T cells and NK cells and promotes antigen cross-presentation. This selectivity has made XCR1 an attractive target for dendritic cell-based cancer vaccines, while emerging evidence also links XCL1-XCR1 signaling to neuroinflammation and pain. Despite its therapeutic […]
- by Yu, Z. H., Siegel, J. B., Morrow, E. R.Metastatic melanoma is an aggressive cutaneous malignancy frequently driven by the oncogenic V600E mutation within the BRAF kinase. While first-generation Type IS BRAF inhibitors, such as dabrafenib, are currently prescribed to target this specific molecular vulnerability, paradoxical MAPK pathway activation, and acquired drug resistance necessitate the continuous development of structurally optimized lead molecules. In this study, chemical intuition, bioisosteric replacement, and computational molecular docking were employed to propose two novel BRAFV600E drug candidates. The proposed therapeutics, engineered to incorporate constrained […]
- by Alimoradi, H., Panahpour, A., Fallah, A., Delporte, C.Inducible nitric oxide synthase (iNOS) is frequently overexpressed in inflammatory disorders and solid tumors, where sustained nitric oxide (NO) production promotes angiogenesis, tumor progression, and resistance to therapy. Despite promising preclinical results, the clinical translation of iNOS inhibitors remains limited by poor tumor selectivity, rapid systemic clearance, and off-target toxicities. To address these challenges, we developed a protease-responsive polymeric iNOS-inhibiting prodrug (ProCIP) designed for localized activation within protease-rich pathological microenvironments. ProCIP was synthesized from poly(ethylene glycol)-poly(L-glutamate) and functionalized with amidine-based […]
- by Saxena, U., Shahapur, S., Mehboob, S., Jadhav, P., Samal, T., Kadiyala, G., Gorantla, M.Fructooligosaccharides (FOS) are prebiotic fibers that influence gut microbiota and host metabolic function. In a diet-induced obesity (DIO) mouse study, FOS supplementation was compared with PBS-treated obese controls. Blood glucose was markedly lower at Day 42 (221.9 {+/-} 7.8 vs 138.3 {+/-} 9.0 mg/dL), and remained lower at Day 56. FOS reduced body-weight gain from 8.4 {+/-} 0.9 g in PBS controls to 2.6 {+/-} 0.2 g, corresponding to an approximate 69.5% reduction in gain over Days 1-70. Cumulative feed […]
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