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- Molecular and cellular mechanisms of ioxynil and diethylstilestrol disruption of cardiac and thyrocyte development and homeostasisPublication . Li, Yifeng; Power, Deborah M.Endocrine disrupting chemicals (EDCs) are compounds that interfere with endocrine systems, induce alterations in their functionality, and give rise to numerous adverse effects that have been documented in animals and ecosystems. The herbicide ioxynil (IOX) and the synthetic estrogen diethylstilbestrol (DES) are two chemicals still in use, which are environmentally relevant contaminants that act as EDCs. In humans, prenatal exposure to DES is associated with an increased incidence and prevalence of cardiac defects. IOX may disrupt the thyroid system by binding to transthyretin (TTR) and provoke thyroid tumors in rats. The main objective of this thesis was to determine how IOX and DES disrupt the crosstalk between the developing thyroid gland and cardiovascular system in zebrafish. An invertebrate bioindicator species, Mytilus coruscus, was included in the study to comprehend the effects of IOX and DES on a bivalve and contribute to a broader understanding of endocrine disruption in both invertebrate and vertebrate organisms. The core achievements were a) characterization of heart function and cardiovascular and thyroid development in IOX- and DES-exposed zebrafish embryos. Transcriptome analysis of vascular endothelial cells of zebrafish embryos that elucidated compound-specific molecular effects associated with endothelial functions; b) identification of the effects of IOX and DES on the physiology of the heart and thyroid in juvenile zebrafish; c) characterization of the effects of IOX and DES on cardiac performance and shell growth of juvenile M. coruscus. Transcriptome analysis of juveniles revealed genes related to cardiac function, neuroendocrine regulation, and detoxification were affected. The findings revealed that IOX and DES exposure had a disruptive effect at a molecular and functional level on the cardiovascular system of a vertebrate (zebrafish) and an invertebrate (M. coruscus), suggesting that these chemicals function as cardiovascular disruptors in both phyla. Overall, the study highlights for the first time the potential at both a molecular and functional level of adverse outcomes for both fish and bivalves of exposure to IOX and DES in the environment, suggesting they are EDCs with broad impacts across multiple organisms.
- ZnO noparticles normalize pancreas function via the GLP-1 and oxidative stress pathways in diabetic ratsPublication . Mirzaei, Fatemeh; Jalili, Cyrus; Khodadadi, Iraj; Hosseini, Nashmin Fayazi; MAJDOUB, Nesrine; Naseri, Nima; Mirzaei, Amir; Abbasi, EbrahimThis experiment was carried out to investigate the effects of ZnO nanoparticles (ZnO NPs) on metabolic parameters, oxidative stress, apoptosis, and pathophysiological alterations of the pancreas in diabetic rats. Nanoparticle was synthesized and its characterizations were determined. We evaluate the toxicity and useful dosage of the ZnO NPs in Wistar male rats. Our experiment showed that 5 mg/kg had a useful effect and was not toxic. Hence, in the next step, the Wistar male rats were randomly divided into 3 groups as follows: (1) control rats (C); (2) diabetic rats (D), (3) diabetic rats received 5 mg/kg NP. After 4 weeks, animals were sacrificed, and blood chemical factors were measured. The oxidative stress, inflammatory, and apoptosis pathways were evaluated. Insulin and glucagon-like peptide-1 (GLP-1) mass was evaluated by immunofluorescence. The morphological changes were evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, hematoxylin and eosin (H&E), and aldehyde fuchsin. ZnO NP acts as an insulin sensitizer and normalizes blood glucose, GLP-1 levels as well as apoptosis, oxidative stress, and inflammatory pathway gene expression in diabetic rats. ZnO NP also alleviates the pathological alterations in the pancreas. This study showed that a low dose of ZnO NPs protects pancreatic β cells from oxidative stress and apoptosis. Administration of ZnO NP also normalized the pathophysiological alteration of the pancreas, thus normalizing metabolic abnormality.
- Chromenone derivatives as CRM1 inhibitors for targeting glioblastomaPublication . Princiotto, Salvatore; Jiménez, Lucía; Domínguez, Lucía; Sequeira, João G. N.; Mourato Paulo, Cristiana Isabel; Orea-Soufi, Alba; da Silva Santos, Bruno Filipe; Dallavalle, Sabrina; Machuqueiro, Miguel; Ferreira, Bibiana; Link, WolfgangGlioblastoma (GBM) is one of the most aggressive and deadly cancers. Due to the complexity and redundancy within signaling networks in GBM, targeted inhibitors of specific pathways have shown only limited success. The nuclear export receptor chromosome region maintenance 1 (CRM1) has recently emerged as a promising therapeutic target, as its inhibition can simultaneously disrupt multiple key oncogenic drivers. Herein, whether chromenone derivatives, known for detecting thiol-containing molecules, can function as CRM1 inhibitors is explored. Several chromenonebased derivatives are synthesized and it is demonstrated that they inhibit CRM1-driven nuclear export in a structure- and dose-dependent manner. A preliminary structure–activity relationship is established, providing a rationale for selective CRM1 binding based on molecular docking studies. Additionally, it is showed that the active chromenone derivatives effectively inhibit the nuclear export of endogenous nuclear export signal-containing substrates in GBM cells. Several of these compounds exhibit selective cytotoxicity againstGBM cell lines, highlighting their potential as targeted therapies for GBM.