Archives of Virology, Год журнала: 2023, Номер 169(1)
Опубликована: Дек. 11, 2023
Язык: Английский
Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)
Опубликована: Апрель 4, 2024
Abstract NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like that covalently attached to a lysine residue of substrate through process known as neddylation, catalyzed by the enzyme cascade, namely activating (E1), conjugating (E2), and ligase (E3). The substrates neddylation are categorized into cullins non-cullin proteins. Neddylation activates CRLs (cullin RING ligases), largest family E3 ligases, whereas alters their stability activity, well subcellular localization. Significantly, pathway and/or many abnormally activated or over-expressed in various human diseases, such metabolic disorders, liver dysfunction, neurodegenerative cancers, among others. Thus, targeting becomes attractive strategy for treatment these diseases. In this review, we first provide general introduction on its biochemical regulation, crystal structures enzymes complex with cullin substrates; then discuss how governs key biological processes via modification substrates. We further review literature data dysregulated several particularly cancer, followed outline current efforts discovery small molecule inhibitors promising therapeutic approach. Finally, few perspectives were proposed extensive future investigations.
Язык: Английский
Процитировано
35
MedComm, Год журнала: 2024, Номер 5(10)
Опубликована: Сен. 25, 2024
Ubiquitination is an enzymatic process characterized by the covalent attachment of ubiquitin to target proteins, thereby modulating their degradation, transportation, and signal transduction. By precisely regulating protein quality quantity, ubiquitination essential for maintaining homeostasis, DNA repair, cell cycle regulation, immune responses. Nevertheless, diversity enzymes extensive involvement in numerous biological processes contribute complexity variety diseases resulting from dysregulation. The relies on a sophisticated system, domains, receptors, which collectively impart versatility pathway. widespread presence highlights its potential induce pathological conditions. Ubiquitinated proteins are predominantly degraded through proteasomal also plays key role localization transport, as well inflammatory pathways. This review systematically delineates roles genomic stability, cellular proliferation, Furthermore, mechanisms implicated various pathologies, alongside current modulators discussed. Enhancing our comprehension aims provide novel insights into involving propose innovative therapeutic strategies clinical
Язык: Английский
Процитировано
7
Molecules, Год журнала: 2024, Номер 29(17), С. 4280 - 4280
Опубликована: Сен. 9, 2024
In this review we explore innovative approaches in the treatment of hematologic cancers by combining various therapeutic modalities. We discuss synergistic potential inhibitors targeting different cellular pathways with immunotherapies, molecular therapies, and hormonal therapies. Examples include PI3K proteasome inhibitors, NF-κB immunotherapy checkpoint neddylation therapies tumor microenvironment. Additionally, use small molecules peptide cancer treatment. These multidimensional combinations present promising strategies for enhancing efficacy overcoming resistance mechanisms. However, further clinical research is required to validate their effectiveness safety profiles patients.
Язык: Английский
Процитировано
6
Molecules, Год журнала: 2025, Номер 30(3), С. 666 - 666
Опубликована: Фев. 3, 2025
Oxazolo[5,4-d]pyrimidines have been found to exhibit a wide range of biological activities, including the inhibition various enzymes and signaling pathways associated with carcinogenesis. The objective this review is demonstrate that oxazolo[5,4-d]pyrimidine scaffold represents valuable structure for design novel anticancer therapies. article provides comprehensive overview chemical pharmacological properties derivatives, drawing upon literature international patents from 1974 until present. Notably, explores structure–activity relationships (SAR) view enhancing therapeutic efficacy oxazolo[5,4-d]pyrimidines.
Язык: Английский
Процитировано
0
Theriogenology, Год журнала: 2025, Номер 237, С. 99 - 109
Опубликована: Фев. 18, 2025
Язык: Английский
Процитировано
0
Hematology, Год журнала: 2025, Номер 30(1)
Опубликована: Март 18, 2025
This study systematically explored the role of NEDD8 in pediatric acute myeloid leukemia (AML) through patient sample analysis, database mining, and vitro experiments. Our results demonstrated that was significantly overexpressed newly diagnosed AML patients associated with poor survival outcomes. Functional enrichment analysis TARGET further revealed a strong correlation between cancer-related pathways. In experiments showed knockdown inhibited proliferation cells (THP-1 MV4-11) induced cell cycle arrest. Collectively, these findings highlight critical pathogenesis suggest its potential as both prognostic biomarker therapeutic target.
Язык: Английский
Процитировано
0
Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер unknown, С. 151703 - 151703
Опубликована: Март 1, 2025
Язык: Английский
Процитировано
0
Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(14)
Опубликована: Март 31, 2025
Gamma Secretase Inhibitors (GSIs) effectively block oncogenic Notch homolog-1 (NOTCH1), a characteristic feature of T cell acute lymphoblastic leukemias (T-ALL). However, their clinical application has been stalled by the induction severe gastrointestinal toxicity resulting from inhibition NOTCH signaling in gut, which translates into increased goblet differentiation. Genome-wide CRISPR loss-of-function screen colon cancer line LS174T identified neddylation pathway as main regulator differentiation upon NOTCH1 inhibition. Consistently, pharmacologic with small molecule inhibitor MLN4924, rescued GSI-induced cells. Mechanistically, MLN4924 increases protein stability Hairy and enhancer split-1, direct transcriptional target key absorptive secretory fate decisions. Combined treatment GSI murine Notch1 -dependent model T-ALL led to leukemia regression improved overall survival absence gut toxicity. Overall, these results support combined targeting pathways for NOTCH1-induced T-ALL.
Язык: Английский
Процитировано
0
Life, Год журнала: 2024, Номер 14(3), С. 400 - 400
Опубликована: Март 18, 2024
Cancer therapy can result in acute cardiac events, such as coronary artery spasm, myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT prolongation, torsades de pointes, pericardial effusion, and hypotension, well chronic conditions, hypertension, systolic diastolic left ventricular dysfunction presenting clinically heart failure or cardiomyopathy. In cardio-oncology, when referring to toxicity cardiovascular hypersensitivity, there is a great deal of misunderstanding. When dose-related side effect continues even after the causative medication stopped, it referred cardiotoxicity. A fibrotic response ultimate outcome toxicity, which defined adverse impact that lasts treatment stopped. Cardiotoxicity occur single brief exposure. On other hand, term hypersensitivity describes an inflammatory reaction not dose-dependent, at any point during therapy, very low dosages, present Kounis syndrome. It may also be accompanied by anti-drug antibodies tryptase levels. this comprehensive review, we current views on together with reviewed literature chemotherapeutic agents inducing reactions. Cardiac seems pathophysiologic basis syndromes syndrome, myocarditis caused cancer therapy.
Язык: Английский
Процитировано
3
Biochemical Pharmacology, Год журнала: 2024, Номер 223, С. 116198 - 116198
Опубликована: Апрель 6, 2024
Язык: Английский
Процитировано
3