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Nature Communications Jun 2024Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly...
Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Acetylation; Poly(ADP-ribose) Polymerase Inhibitors; Spliceosomes; Cell Line, Tumor; Phthalazines; Exons; Piperazines; Animals; BRCA1 Protein; Depsipeptides; Mice; DNA Damage; Gene Expression Regulation, Neoplastic
PubMed: 38890388
DOI: 10.1038/s41467-024-49573-7 -
Journal of Microbiological Methods Jun 2024The mucin-degrading gut commensal Akkermansia muciniphila (A. muciniphila) negatively correlates with various diseases, including metabolic disorders, neurodegenerative...
The mucin-degrading gut commensal Akkermansia muciniphila (A. muciniphila) negatively correlates with various diseases, including metabolic disorders, neurodegenerative disorders, and cancers, through interacting with host receptors by diverse molecules. Still, their exact metabolic capability within the nutrient-rich environment (such as in the human gut) is not fully characterized. Therefore, in the present study, we investigated the comprehensive metabolome and lipidome of A. muciniphila after supplementation of four major gut microbial nutrients: mucin, inorganic salts, bile salts, and short-chain fatty acids (SCFAs). Our results showed that mucin is the predominant driver of the different lipidomic and metabolomic profiles of A. muciniphila, and it promotes the overall growth of this bacteria. While the addition of inorganic salts, bile salts, and SCFAs was found to inhibit the growth of A. muciniphila. Interestingly, inorganic salts affected the purine metabolism in A. muciniphila cultures, while adding bile salts significantly increased the production of other bile acids and N-acyl amides. Lastly, SCFAs were identified to alter the A. muciniphila energy utilization of triglycerides, fatty acyls, and phosphatidylethanolamines. To our knowledge, this is the first study to examine the comprehensive lipidome and metabolome of A. muciniphila, which highlights the importance of nutritional impacts on the lipidome and metabolome of A. muciniphila and hence providing foundational knowledge to unveil the potential effects of A. muciniphila on host health.
PubMed: 38889842
DOI: 10.1016/j.mimet.2024.106975 -
Archiv Der Pharmazie Jun 2024Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the...
Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the quinolone system and to restrict the conformational flexibility of the aminopropanol substructure in a cyclopentane system. The designed ligands were synthesized in an eight-step sequence starting with terephthalaldehyde (5). Key steps pf the synthesis were the intramolecular Friedel-Crafts acylation of propionic acids 10 to yield the cyclopenta[g]quinolinediones 11 and the Mannich reaction of diketone 11a followed by conjugate addition at the α,β-unsaturated ketone 12a. Although the quinolones 13a, 15a, and 16a contain an H-bond donor group (secondary lactam) as ifenprodil and Ro 25-6981, they show only moderate GluN2B affinity (K > 410 nM). However, the introduction of lipophilic substituents at the quinolone N-atom resulted in more than 10-fold increased GluN2B affinity of the benzyl and benzyloxymethyl derivatives cis-13c (K = 36 nM) and 13e (K = 27 nM). All compounds are selective over the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The benzyl derivative 13c showed six- and threefold selectivity over σ and σ receptors, respectively.
PubMed: 38889396
DOI: 10.1002/ardp.202400279 -
Proceedings of the National Academy of... Jun 2024Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alterations of these...
Aberrant regulation of chromatin modifiers is a common occurrence across many cancer types, and a key priority is to determine how specific alterations of these proteins, often enzymes, can be targeted therapeutically. MOZ, a histone acyltransferase, is recurrently fused to coactivators CBP, p300, and TIF2 in cases of acute myeloid leukemia (AML). Using either pharmacological inhibition or targeted protein degradation in a mouse model for MOZ-TIF2-driven leukemia, we show that KAT6 (MOZ/MORF) enzymatic activity and the MOZ-TIF2 protein are necessary for indefinite proliferation in cell culture. MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors, augmenting their high expression. Furthermore, transcription levels in MOZ-TIF2 cells positively correlate with enrichment of histone H3 propionylation at lysine 23 (H3K23pr), a recently appreciated histone acylation associated with gene activation. Unexpectedly, we also show that MOZ-TIF2 and MLL-AF9 regulate transcription of unique gene sets, and their cellular models exhibit distinct sensitivities to multiple small-molecule inhibitors directed against AML pathways. This is despite the shared genetic pathways of wild-type MOZ and MLL. Overall, our data provide insight into how aberrant regulation of MOZ contributes to leukemogenesis. We anticipate that these experiments will inform future work identifying targeted therapies in the treatment of AML and other diseases involving MOZ-induced transcriptional dysregulation.
Topics: Animals; Mice; Histones; Histone Acetyltransferases; Leukemia, Myeloid, Acute; Humans; Disease Models, Animal; Nuclear Receptor Coactivator 2; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Developmental; Oncogene Proteins, Fusion
PubMed: 38889153
DOI: 10.1073/pnas.2405905121 -
RSC Advances Jun 2024This study presents the synthesis and characterization of phenazinium dyes with absorption ranging from red to far-red, as well as emission extending into the far-red to...
This study presents the synthesis and characterization of phenazinium dyes with absorption ranging from red to far-red, as well as emission extending into the far-red to near-infrared (NIR) region. The procedure involves the post-functionalization of a triamino-phenazinium that was recently reported as a theranostic agent. The introduction of electron-withdrawing moieties is accomplished through acylation or aromatic nucleophilic substitution. For one of the obtained products, a further substitution step could be achieved with primary amines to tune the electron density of the phenazinium core. The isolated dyes exhibit promising features that hold potential for future applications as biological markers or therapeutic agents.
PubMed: 38887642
DOI: 10.1039/d4ra03245d -
Beilstein Journal of Organic Chemistry 2024Tandem Diels-Alder reactions are often used for the straightforward formation of complex natural compounds and the fused polycyclic systems contained in their...
Tandem Diels-Alder reactions are often used for the straightforward formation of complex natural compounds and the fused polycyclic systems contained in their precursors. In the second step of this reaction, regio- and stereochemically controlled intramolecular cyclization leads to the formation of versatile nitrogen-containing tricyclic systems. However, these useful organic transformations are usually carried out in highly toxic organic solvents such as benzene, toluene, chloroform, etc. Despite recent efforts by 'green chemists', synthetic chemists still use these traditional toxic organic solvents in many of their reactions, even though safer alternatives are available. However, in addition to the harmful effects of these petrochemical solvents on the environment, the prediction that their resources will run out in the near future has led 'green chemists' to explore solvents that can be derived from renewable resources and used effectively in various organic transformations. In this context, we have shown for the first time that the 100% atom-economical tandem Diels-Alder reaction between aminofuranes and maleic anhydride can be carried out successfully in vegetable oils and waxes. The reaction was successfully carried out in sunflower seed oil, olive oil, oleic acid and lauryl myristate under mild reaction conditions. A series of epoxyisoindole-7-carboxylic acid and bisepoxyisoindole-7-carboxylic acids were obtained in good yields after a practical isolation procedure. The results obtained in this study demonstrate the potential of vegetable oils and their renewable materials to provide a reaction medium that is more sustainable than conventional organic solvents in cascade Diels-Alder reactions and can be used repeatedly without significant degradation. These materials also allow the reaction to be completed in less time, with less energy consumption and higher yields.
PubMed: 38887569
DOI: 10.3762/bjoc.20.114 -
Methods in Enzymology 2024The modulation of biology utilizing foldamers has flourished over the last few decades thanks to their overwhelming promise in their applications in molecular design,...
The modulation of biology utilizing foldamers has flourished over the last few decades thanks to their overwhelming promise in their applications in molecular design, catalysis, supramolecular, and rational design. However, the application of peptidomimetics is still restricted due to the limited availability of molecular frameworks and folding propensities. To broaden the scope of foldameric peptidomimetics we proposed the development of sulfonyl-γ-AApeptides-the oligomers of sulfonyl-γ-N-acylated-N-aminoethyl (AA) amino acids, a unique unnatural scaffold that possesses promising potential to modulate protein-protein interactions. In this chapter, the overall process of design, synthesis, and function of sulfonyl-γ-AApeptides is briefly reviewed for the use of unnatural foldamers to modulate PPIs.
Topics: Peptidomimetics; Peptides; Humans; Protein Folding; Amino Acids; Protein Binding
PubMed: 38886034
DOI: 10.1016/bs.mie.2024.04.021 -
Methods in Enzymology 2024Chemical modifications to proteins have wide applications. They may be used in, for example, the production of biopharmaceuticals and fluorescent probes. Despite their...
Chemical modifications to proteins have wide applications. They may be used in, for example, the production of biopharmaceuticals and fluorescent probes. Despite their importance, highly regioselective chemical protein modifications are often challenging to achieve. We have developed two highly selective methods for protein acylation using poly-His tags inserted either at the N-terminus or in combination with a specific Lys residue. For this, we used an N-terminal Gly-His (Gly-His tag) or the sequence His-Lys-His (Lys-His tag), respectively. The Gly-His tag directed the acylation to the N-terminal N-amine when reacted with 4-methoxyphenyl esters to yield stable conjugates. Next, the Lys-His tag was developed to allow modifications at the C-terminus or in loop regions of proteins. This gave a high selectivity of acylation of the designated Lys N-amine in the tag over native Lys residues in the protein under mild conditions. Here, we describe the synthesis of aromatic esters carrying different functionalities and reactivity tuning substituents on the phenol. The expression of poly-His tagged proteins, and the procedure for the highly selective peptide and protein acylations are detailed in this contribution. The versatility of these methods has been demonstrated by the attachment of different functionalities such as fluorophores, biotin, and azides to different proteins and an antibody.
Topics: Acylation; Peptides; Histidine; Proteins; Esters
PubMed: 38886029
DOI: 10.1016/bs.mie.2024.04.009 -
International Journal of Biological... Jun 2024In this study, acylated porous Canna edulis starch with varying degrees of substitution (DS) were prepared and employed for stabilizing Pickering emulsions....
In this study, acylated porous Canna edulis starch with varying degrees of substitution (DS) were prepared and employed for stabilizing Pickering emulsions. Subsequently, the fermentation characteristics of them were investigated. Enzymatically produced porous starch (PS) was esterified with acetic, propionic, butyric, or valeric anhydrides, yielding acetylated (PSA-0.116), propionylated (PSP-0.163), butyrylated (PSB-0.304), and valerylated PS (PSV-0.462) with different DS. Scanning electron microscopy revealed the presence of pores and surface micro-particles in the modified PS, confirming successful esterification through characteristic peaks in H NMR and a CO peak at 1736 cm in the FT-IR spectrum. With increasing DS, starch exhibited reduced crystallinity (PSV, 26.61 %), elevated resistant starch content (PSV, 91.63 %), and a higher contact angle (PSV, 87.13°). Acylated PS particles effectively stabilized Pickering emulsions. Pickering emulsions stabilized by acylated PS with higher DS exhibited higher emulsification index and smaller droplet sizes. In vitro fermentation of acylated PS and corresponding stabilized Pickering emulsions fostered short-chain fatty acid production, boosted the relative abundance of beneficial bacteria (Bifidobacterium, Prevotella, etc.) while inhibited the growth of harmful bacteria (Escherichia-Shigella, Comamonas, etc.), maintaining the intestinal microbiota balance. These findings support the potential applications of acylated PS and corresponding stabilized Pickering emulsions in functional foods and drug delivery.
PubMed: 38885854
DOI: 10.1016/j.ijbiomac.2024.133169 -
Chemphyschem : a European Journal of... Jun 2024An electrochemical N-acylation of sulfoximine has been achieved via the coupling of α-keto acids and NH-sulfoximines. This process involves the sequential cleavage of...
An electrochemical N-acylation of sulfoximine has been achieved via the coupling of α-keto acids and NH-sulfoximines. This process involves the sequential cleavage of C-C bond followed by C(sp2)-N bond formation, with the liberation of H2 and CO2 as the by-products. A library of N-aroylated sulfoximines is produced via the coupling of aroyl and sulfoximidoyl radicals by anodic oxidation under constant current electrolysis (CCE). The compatibility of the present protocol has been demonstrated by coupling of various bio-active compounds, such as NH-sulfoximine derived from (-)-borneol, L-menthol, D-glucose derivative, and some commercial drugs such as flurbiprofen, and ibuprofen. This late-stage functionalization highlights the importance of this sustainable protocol. Besides this, various control experiments and detection of H2 evolution have been performed to support the proposed mechanism.
PubMed: 38884606
DOI: 10.1002/cphc.202400599