bims-midomi 2025-10-19 papers

Molecules. 2025 Sep 28. pii: 3908. [Epub ahead of print]30(19):

Multi-Step Synthesis of Chimeric Nutlin-DCA Compounds Targeting Dual Pathways for Treatment of Cancer.

Davide Illuminati, Rebecca Foschi, Paolo Marchetti, Vinicio Zanirato, Anna Fantinati, Claudio Trapella, Rebecca Voltan, Virginia Cristofori.

Chimeric compounds represent a promising strategy in cancer therapy by simultaneously targeting multiple pathways responsible for tumour growth and survival. Their structure comprises two or more pharmacophores connected through suitable chemical linker. These dual or multi-functional drugs can interact with several biological targets for a more pronounced pharmacological effect. In order to identify new multi-targeting agents with anticancer efficacy, we designed and synthesised a series of novel multi-functional molecules by covalently linking antitumor compounds dichloroacetate (DCA) and Nutlin-3a. The design was aimed at addressing two critical events in cancer: (1) the Warburg effect and (2) the dysregulations of protein p53 pathway, both of which are directly linked to the predominant survival and aggressive proliferation of malignant cells. DCA reactivate oxidative phosphorylation by inhibiting mitochondria pyruvate dehydrogenase kinase (PDK), thereby unlocking the Warburg metabolism of cancer cells and its antiapoptosis state. Concurrently, Nutlin-3a restores the protective function of the "genome guardian" p53 protein, by blocking its antagonist oncoprotein E3 ligase MDM2. Chimeric compounds were obtained using a chemoenzymatic multi-step procedure that included a key lipase-catalysed asymmetric reaction. Biological evaluation of the synthesised Nutlin-DCA chimeras in a panel of three cancer cell lines demonstrated promising results in vitro. Specifically, compounds rac-19a, rac-19b, rac-20a, rac-20b and enantioenriched 20a caused a statistically significant reduction in cell viability at micromolar concentrations. These findings suggest that targeting both the Warburg effect and the p53 pathway with a single molecule is a viable approach for future cancer therapeutic development.

Keywords: DCA; Nutlin; cancer research; chemoenzymatic synthesis; chimeric compounds

DOI: https://doi.org/10.3390/molecules30193908

iScience. 2025 Oct 17. 28(10): 113555

The p53 mRNA exhibits riboswitch-like features under DNA damage conditions.

Sa Chen, Lixiao Wang, Laurence Malbert-Colas, Konstantinos Karakostis, Vanesa Olivares-Illana, Sivakumar Vadivel Gnanasundram, Robin Fahraeus.

RNA riboswitch structures control prokaryotic gene expression in response to changes in the cellular environment, but how this concept has evolved in mammalian cells is yet little known. Here, we describe the riboswitch-like features of the p53 mRNA that controls p53 synthesis following DNA damage. The conserved BOX-I stem-loop in the 5' coding sequence acts as an aptamer that controls the folding of a compact downstream MDM2-binding p53 mRNA structure. MDM2 brings the p53 mRNA to the ribosome and promotes p53 synthesis. High-throughput in-cell RNA structural probing and in vitro RNA-RNA and RNA-protein interactions show how the cancer-associated synonymous mutation in codon 22 (CASM22) of the BOX-I aptamer stabilizes the p53 mRNA structure and prevents the formation of the MDM2-binding platform. However, the CASM22 does not affect p53 mRNA folding during the unfolded protein response, demonstrating the specificity by which the CASM22 targets the p53 DNA damage response.

Keywords: Molecular biology; Structural biology

DOI: https://doi.org/10.1016/j.isci.2025.113555

Int J Oral Maxillofac Surg. 2025 Oct 16. pii: S0901-5027(25)01465-1. [Epub ahead of print]

Giant dedifferentiated liposarcoma of the mandible.

K Morishita, T Naruse, N Katase, T Yamada.

Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive malignant soft-tissue tumour with a poor prognosis. This report describes a case of giant DDLPS in the oral cavity, arising in the mandible. A 65-year-old woman was referred to the authors' hospital with a mandibular swelling. A presumptive diagnosis of mandibular malignant tumour (DDLPS; T3N0M0, stage III) was made based on correlation of the clinicopathological features. Before radical surgery, a tracheostomy was performed, as there was narrowing of the pharyngeal cavity due to tumour growth. A bilateral supraomohyoid neck dissection, segmental mandibulectomy, and reconstruction with titanium plates and a free rectus abdominis musculocutaneous flap were performed under general anaesthesia. Neither neoadjuvant nor adjuvant chemoradiotherapy was administered. Immunohistochemistry was positive for MDM2, CDK4, and p16, and genetic testing showed amplification of the MDM2 and CDK4 genes. No evidence of recurrence was observed after 18 months of follow-up.

Keywords: Head and neck neoplasms; Immunohistochemistry; Liposarcoma; Mandible; Mouth

DOI: https://doi.org/10.1016/j.ijom.2025.09.010

J Cell Mol Med. 2025 Oct;29(20): e70771

Unique Genetic and Epigenetic Alterations in Glioblastoma Long-Term Survivors: Insights From Two Clinical Cases.

Elena Anghileri, Evelina Miele, Sara Patrizi, Sabina Barresi, Elisabetta Lazzarini, Luisa Maddaloni, Monica Patanè, Lucia Pedace, Rosina Paterra, Antonio Silvani, Franco Locatelli, Stefano Indraccolo, Bianca Pollo.

The biological mechanisms driving the long survival in glioblastoma (GBM). Five-year long-term survival (LTS) and 10-year survival very long-term survival (VLTS) remain significantly understudied. Here we molecularly detailed two cases. AR10-046 (VLTS) was affected by a giant cell-GBM, classified as the pedHGG_RTK1a subtype according to the v12.5 Heidelberg brain tumor methylation classifier. Somatic and germline MSH6 mutations, typically in Lynch syndrome, and high tumour mutational burden were detected. The copy number variation plots showed chromosome 1q gain and chromosome 13 loss with no other typical GBM alterations. AR10-037 (LTS) suffered from a classical GBM, identified as pedHGG_MYCN subclass. Apart from the canonical chromosome 7 gain and chromosome 10q loss, we observed MDM2 gene amplification and possible rearrangements on chromosome 12 and 18 with the typical aspect of chromothripsis, harbouring two putative new gene fusions: CPSF6::CPM and PTPRR::RAB3IP. We described two patients with peculiar tumour molecular profile, widening the scenario of clinical and molecular variability in such patients.

Keywords: DNA methylation (DNAm) profile; Lynch syndrome (LS); MSH6 mutation; chromothripsis (CT); glioblastoma (GBM); long‐term survival (LTS); very LTS (VLTS)

DOI: https://doi.org/10.1111/jcmm.70771

Adv Sci (Weinh). 2025 Oct 17. e12807

Activation of USP30 Disrupts Endothelial Cell Function and Aggravates Acute Lung Injury Through Regulating the S-Adenosylmethionine Cycle.

Baoyinna Baoyinna, Jinshan He, Jiaxing Miao, Nargis Shaheen, Boyu Xia, Cankun Wang, Qin Ma, Matthew C Bernier, Bryan A Whitson, Nuo Sun, Jing Zhao, Yutong Zhao.

Microvascular dysfunction is a key contributor to the development of acute inflammatory diseases, characterized by heightened vascular hyperpermeability and leukocyte infiltration into interstitial tissues. Despite substantial research efforts, the precise mechanisms remain partially elucidated. Here, it is identified that USP30 is a critical regulator of lung microvascular inflammation and endothelial cell (EC) barrier integrity. Lipopolysaccharide (LPS) induces deubiquitinase activity of USP30. It is demonstrated that USP30 activation exacerbates EC dysfunction. Inhibiting USP30 leads to a 50% attenuation of inflammatory responses in ECs. In vivo, EC-specific USP30-deficient mice exhibit reduced microvascular dysfunction in models of endotoxin-induced and ischemia-reperfusion lung injury. Inhibition of USP30 preserves EC function via a mitophagy-independent mechanism involving the S-adenosylmethionine (SAM) cycle, DNA methylation, and miR-30a-5p expression. Mechanistically, USP30 depletion destabilizes and reduces methionine adenosyltransferase 2A (MAT2A) by deubiquitination, which in turn lowers SAM levels by ≈40%, and decreases global DNA methylation by roughly 35%, thereby resulting in a fourfold upregulation of miR-30a-5p. Elevated miR-30a-5p suppresses MDM2 and NFAT5 expression, contributing to the maintenance of EC function. These findings highlight that targeting USP30 may represent a potential therapeutic strategy warranting further preclinical and clinical exploration in acute lung injury.

Keywords: DNA methylation; SAM cycle; USP30; deubiquitinase; endothelial barrier integrity; miRNA

DOI: https://doi.org/10.1002/advs.202512807