Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Objective: Ovarian cancer is the most lethal gynecological malignancy, but current treatments have not improved overall survival and recurrence rates. New therapies are needed and, in this context, we propose the use of the sodium/iodide symporter (NIS) that enables effective targeted Radioiodide therapy (RAI), as NIS is overexpressed in ovarian cancer.

Methods: Using datasets and patient samples of human ovarian tumors, we determine the expression of NIS and canonical epithelial markers. We characterized NIS expression and function in human derived cell lines and tested the in vivo functional expression of NIS using Single Photon Emission Computed Tomography (SPECT). We also compared the efficacy of RAI versus chemotherapeutic treatments (cisplatin and paclitaxel) in mouse models.

Results: Human ovarian tumors expressed NIS, predominantly in a non-glycosylated form, with plasma membrane localization. Datasets and RNAseq confirmed NIS expression in ovarian epithelial tumors. Functional NIS expression was observed both in vitro and in vivo. In preclinical ovarian cancer mouse models, RAI therapy with ¹³¹I greatly reduced or eliminated tumors, was more effective, and had fewer secondary effects than classical treatments (cisplatin and paclitaxel), although both could be combined.

Conclusions: Our findings highlight that RAI through NIS could serve as a therapeutic agent in ovarian cancer. Additionally, it may enable non-invasive imaging and monitoring of disease progression.

Serous ovarian carcinoma (SOC) is an aggressive disease, characterized by advanced-stage tumors that are often associated with relapse and poor outcomes. Although platinum-based chemotherapy is a cornerstone of the treatment, most of the relapsed tumors become resistant to these agents. We explored organoids derived from SOC malignant effusions to identify targets actionable by epigenetic drugs (epi-drugs) to enhance platinum response. Tumor-derived organoids (TDOs) were established using malignant effusions of SOC patients. Histological and transcriptomic (RNA-Seq) characterization (18 TDOs versus 7 normal ovarian samples) was performed, followed by cross-validation with external RNA-Seq datasets (337 SOC samples, 4 TDOs, and 180 normal tissues). Predicted interactions between long noncoding RNAs (lncRNAs) and epigenetic effectors were investigated. We selected the epi-drugs decitabine and tazemetostat, whose targets were overexpressed in SOC, to treat carboplatin-resistant SOC cell lines and TDOs. Subsequently, these models were challenged with carboplatin. Twelve lncRNAs and 168 protein-coding genes differentially expressed were involved in epigenetic regulation. Abnormal expression levels of lncRNA MEG3 and epigenetic effectors DNMT3B and EZH2 were confirmed in external datasets. Increased carboplatin sensitivity and MEG3 upregulation were observed after treating the cell lines and TDOs with epi-drugs. Altogether, our findings provide novel insights into using organoids derived from malignant effusions as preclinical models and hint at potential targets for overcoming platinum resistance in SOC.

Metabolic disorders, such as obesity, are highly related to neurodegenerative diseases through neuroinflammation. Pleiotrophin (PTN) is a cytokine that is upregulated in various neuroinflammatory disorders. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. To investigate the role of PTN, a HFD-induced obesity model was used in Ptn genetically deficient (Ptn^-/-) mice. To investigate the role of RPTPβ/ζ, we administered the selective inhibitor of RPTPβ/ζ, MY10, while mice were fed with HFD. The data demonstrate that Ptn deletion protects against both HFD-induced obesity and HFD-induced memory loss, whereas pharmacological inhibition of RPTPβ/ζ produces the opposite effects. In addition, HFD induced astrogliosis and microgliosis. However, Ptn deletion led to the absence of these glial responses, whereas MY10 reversed HFD-induced microgliosis. Finally, we demonstrated that PTN/RPTPβ/ζ signaling is important for adult hippocampal neurogenesis (AHN), the formation and maintenance of perineuronal nets (PNNs), and is involved in the regulation of the effects of HFD in these processes. The data demonstrate a key role of the PTN/RPTPβ/ζ signaling pathway in the connection between obesity, cognitive decline, and the associated brain alterations. The data suggest therapeutic potential in treating brain injuries associated with metabolic disorders, including mild cognitive impairment and dementia, through pharmacological modulation of this pathway.

Although murine double minute 2 (MDM2) inhibitors are known for their anti-cancer effects via p53 activation, their potential role in bone regeneration remains largely unexplored. In this study, we systematically screened 22 MDM2 inhibitors and identified serdemetan as the best candidate according to its dual functionalities of promoting osteogenesis and inhibiting osteoclastogenesis. Therefore, we adopted a drug repurposing study to determine the impact of MDM2 pharmacological inhibition on osteogenic and osteoclast activities in vitro and in vivo. Specifically, we validated the pro-osteogenic and anti-osteoclastic effects of serdemetan using human bone marrow stromal cells (hBMSCs) and bone marrow-derived macrophages (BMM), then integrated bulk RNA-sequencing data to elucidate the possible molecular mechanisms underlying biomineralization. Serdemetan significantly enhanced osteogenic differentiation and mineralization in hBMSCs and potently suppressed osteoclast formation, actin ring assembly, and bone resorption in BMMs. Transcriptomic profiling revealed robust activation of the p53 signaling pathway and upregulation of osteogenic genes in hBMSCs. Moreover, serdemetan downregulated osteoclast-related markers and enhanced autophagy-associated gene expression in BMMs, suggesting a p53-mediated mechanism of dual regulation. Regarding preclinical efficacy, serdemetan markedly accelerated bone healing in a rat calvarial defect model and restored trabecular bone architecture in an ovariectomy-induced osteoporosis model, demonstrating similar therapeutic efficacy to alendronate. In summary, we present serdemetan as a promising candidate for bone regeneration through regulation of the MDM2-p53 axis, offering new therapeutic possibilities beyond its established role in oncology.

In the present study, we introduce thiosemicarbazone derivatives with high antiproliferative activity against glioblastoma cells and high selectivity against healthy cells. The cellular studies were performed on a 3D spheroid model, which more closely reflects the conditions of an actual tumor. The tested thiosemicarbazone derivatives form complexes with iron ions, triggering the generation of reactive oxygen species, leading to cell death. The multitarget mechanism of action manifests through inhibition of the insulin receptor and the impact on iron metabolism and the disruption in redox homeostasis inducing oxidative stress in the cell. An additional advantage of the tested thiosemicarbazone derivatives is their ability to pass through the blood-brain barrier, which is crucial in the case of brain tumors. The effectiveness of the therapy was confirmed in a fish in vivo model, in which a reduction in tumor size in xerographs was recorded while maintaining minimal toxicity on a Zebrafish model. These results render the studied compounds attractive as potential drugs for therapy against glioblastoma.

Muscarinic acetylcholine receptors (mAChRs) are key regulators of diverse physiological processes and longstanding therapeutic targets. Building on the long-acting antagonist KH-5, we synthesised and evaluated a series of 4-(hexyloxy)benzoate derivatives and their quaternary N-methylated analogues to explore how structural modifications influence receptor affinity and the duration of functional antagonism. Our structure-activity analysis revealed that introducing a rigid azabicyclo[2.2.2]octan-1-ium group boosted binding affinity (up to 250-fold compared to parental compounds) yet reduced the half-life of functional antagonism. In contrast, analogues with moderate flexibility maintained high potency while preserving longer receptor residence time. Computational docking and molecular dynamics (MD) simulations demonstrated that stable hydrogen bonding with residue N6.52 and salt-bridge formation with D3.32 were critical for sustained ligand binding to the receptor, with MD-derived metrics outperforming docking energies in predicting biological activity. Crucially, a positively charged nitrogen and a 4-hexyloxy substituent are essential features for high-affinity binding and prolonged antagonism. Shortening the alkyl chain resulted in a marked loss of affinity and abolished sustained activity. These findings underscore the need to balance molecular rigidity with conformational flexibility and charge distribution in the design of long-residence mAChR antagonists, offering a framework for further development of mAChR-targeted long-acting antagonists.