Third-generation analogues of Guttiferone AHozain, Cottet, Fromentin
et alBioorg Med Chem Lett (2025) 122, 130186
Abstract: This study introduces third-generation derivatives of guttiferone A, designed to enhance both bioactivity and selectivity against Plasmodium falciparum and Trypanosoma brucei. Following an optimized synthetic route, two dioxolane derivatives of 3,16-oxyguttiferone A were prepared: 14-monodioxolane-3,16-oxyguttiferone A (3) and 13,14-bisdioxolane-3,16-oxyguttiferone A (4). Biological evaluation revealed compound 3 to be the most effective, with a selectivity index (SI) of 457.1 against Trypanosoma brucei brucei strain and 57.1 against P. falciparum, significantly outperforming its precursors. Compound 4 also demonstrated substantial activity with an SI of 143.8 against T. brucei. These results highlight the potential of targeted structural modifications, particularly monodioxolane substitution, to improve the pharmacological profile of guttiferone A derivatives.Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.
Capillariid diversity in archaeological material from the New and the Old World: clustering and artificial intelligence approachesBorba, Gurjão, Martin
et alParasit Vectors (2025) 18 (1), 104
Abstract: Capillariid nematode eggs have been reported in archaeological material in both the New and the Old World, mainly in Europe and South America. They have been found in various types of samples, as coprolites, sediments from latrines, pits, or burial. Modern parasitological records show that around 300 species of capillariids have been described in all vertebrate taxa, including humans, making it a very diversified group. The main proposal of this work is to characterize and identify capillariid eggs found in archaeological sites from Europe and Brazil.A total of 39 samples of archeological sites from Europe, deposited in the paleoparasitological collection of the University Marie & Louis Pasteur, Besançon, France was analyzed. In addition, 80 coprolites from the pre-Colombian archaeological site Gruta do Gentio II, Brazil, deposited in the Paleogenetic Laboratory at Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, were evaluated. Samples were treated according to the protocols of each laboratory and then analyzed under light microscopy. Capillariid eggs were classified according to length, width, plugs, and eggshell sizes, and statistical analysis of the morphometric dataset was performed. Using a reference dataset of specimens provided by both Institutional Collections, three approaches to species identification were applied: discriminant analysis, hierarchical clustering, and artificial intelligence/machine learning.A total of 10 samples from Europe and 4 from Brazil were positive for capillariid eggs, showing 13 different morphotypes. As European samples were mainly collected from latrines and pits, parasite-host information was absent, and consequently, species identification was impaired. In contrast, the availability of host information rendered the identification of capillariid species for the Brazilian coprolites. The new methodology indicates capillariid species identified on various samples, resulting in the presence of Capillaria exigua (Dujardin, 1845) in feline coprolite, Baruscapillaria resecta (Dujardin, 1845) in opossum, and Aonchotheca bovis (Schnyder, 1906) in bovid, in the Brazilian site, while in European sites, Capillaria venusta (Freitas e Mendonça, 1958), Aonchotheca myoxinitelae (Diesing, 1851), Eucoleus madjerdae (Bernard, 1964), and Baruscapillaria spiculata (Freitas, 1933) were found.The study provides new results by applying innovative methodologies for parasite identification and gaining insights into the past host (human or animal)/parasite relationships.© 2025. The Author(s).
Melanoma Cell Adhesion Molecule Plays a Pivotal Role in Proliferation, Migration, Tumor Immune Microenvironment, and Immunotherapy in Colorectal CancerZhou, Liu, Yu
et alCancer Med (2025) 14 (5), e70740
Abstract: MCAM, alternatively referred to as CD146, is an integral membrane glycoprotein belonging to the immunoglobulin superfamily. However, its importance in the tumorigenesis of colorectal cancer is still partially understood. Therefore, this study was designed to investigate the significance of MCAM in colorectal cancer.MCAM expression was analyzed by TCGA and GEO databases. qRT-PCR and IHC analysis were conducted to validate MCAM expression in patient tissues. The tumor-inhibiting ability of MCAM was further assessed by CCK-8 assay, colony formation assay, and wound-healing assay. qRT-PCR and WB analysis were conducted to evaluate the expression of EMT markers and MMP2/9. qRT-PCR analysis was utilized to detect the polarization status of macrophages. Kaplan-Meier curve, univariate, and multivariate cox analyses were employed to verify the ability of MCAM in prognosis prediction. TIDE scores were used to assess the impact of MCAM on immunotherapy.The expression of MCAM was significantly downregulated in CRC, and low MCAM expression revealed poor prognosis in CRC patients. Moreover, MCAM overexpression inhibited the proliferation, migration, and invasive ability of CRC cells. Additionally, MCAM overexpression suppressed N-cadherin and MMP2/9 expression. Furthermore, MCAM impacted M1 macrophage polarization. MCAM is an independent predictor of CRC patient prognosis through Cox regression analysis. Lastly, TIDE score analysis indicated that elevated expression of MCAM increased immunotherapy efficacy.The findings of this research suggest that MCAM impacts M1 macrophage polarization and enhances immunotherapy efficacy, underscoring its potential as a therapeutic target for colorectal cancer.© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.
Lasso peptides sviceucin and siamycin I exhibit anti-virulence activity and restore vancomycin effectiveness in vancomycin-resistant pathogensBoudrioua, Baëtz, Desmadril
et aliScience (2025) 28 (3), 111922
Abstract: Antibiotic resistance is a major threat to human health and new drugs are urgently needed. Ideally, these drugs should have several cellular targets in pathogens, decreasing the risk of resistance development. We show here that two natural ribosomally synthesized lasso peptides (LPs), sviceucin and siamycin I, (1) abolish bacterial virulence of pathogenic enterococci, (2) restore vancomycin clinical susceptibility of vancomycin-resistant (VR) enterococci in vitro and in a surrogate animal model, and (3) re-sensitize VR Staphylococcus aureus. Mode of action (MoA) analyses showed that they do so by inhibiting the histidine kinases (HKs) FsrC and VanS controlling these phenotypes. Strains resistant to the vancomycin/LP combination were difficult to obtain, and were still fully susceptible to the anti-virulence effect of the LPs, highlighting the advantage of multiple targets. Together with the highly sought-after MoA as HK inhibitors, such properties make these lasso peptides promising candidates for the development of next generation antibiotics.© 2025 The Authors.
膜杰作
Star Staining
