Current Opinion in Biotechnology, Год журнала: 2024, Номер 91, С. 103248 - 103248
Опубликована: Дек. 31, 2024
Язык: Английский
Trends in Endocrinology and Metabolism, Год журнала: 2025, Номер unknown
Опубликована: Апрель 1, 2025
Язык: Английский
Процитировано
0
European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 285, С. 117247 - 117247
Опубликована: Янв. 9, 2025
Clear cell renal carcinoma (ccRCC) presents substantial therapeutic challenges due to its molecular heterogeneity, limited response conventional therapies, and widespread drug resistance. Recent advancements in research have identified novel targets, such as BUB1B, which has been through global transcriptomic profiling gene co-expression network analysis critical ccRCC progression. In this study, we synthesized 40 derivatives of TG-101209 modulate BUB1B expression activity, leading the induction apoptosis Caki-1 cells. The structures all compounds were confirmed via 1H 13C NMR mass spectrometry. Computational docking studies conducted using Schrödinger Maestro software. efficacy on viability was screened MTT assay further validated by LDH assay. target protein apoptosis-related proteins analyzed western blotting. activity assessed an enzymatic assay, compound binding evaluated a cellular thermal shift (CETSA). results indicated that four (7h, 8h, 8i, 8j) demonstrate stronger interactions better conformational fit within cavity, improved affinity. These also exhibited more potency reducing cells compared TG-101209. particular, 8h most effective, exhibiting strongest inhibitory effect inducing apoptosis. Compound demonstrated intracellular with similar TG-101209, but different moiety destabilizes structure, whereas stabilizes it. conclusion, destabilizing apoptosis, shows promise potent candidate for clear treatment.
Язык: Английский
Процитировано
0
Опубликована: Янв. 30, 2025
Excessive consumption of sucrose, in the form sugar-sweetened beverages, has been implicated pathogenesis metabolic dysfunctionLassociated fatty liver disease (MAFLD) and other related syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role response to dietary stressors, it was demonstrated that inhibition JNK could potentially be used treatment MAFLD. However, intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water investigated potential by employing network analysis based on transcriptome profiling obtained from hepatic extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, brain. Our data demonstrate JNK-IN-5A effectively reduces circulating triglyceride accumulation inflammation subjected sucrose consumption. Coexpression genome-scale modelling reveal overconsumption primarily induces transcriptional dysfunction acid oxidative metabolism which are largely rectified after at clinically relevant dose. Skeletal muscle exhibited minimal changes but underwent substantial adaptation following inhibition. Overall, our provides novel insights into molecular basis exerts its effect metabolically active Furthermore, findings underpin critical development diet-induced steatosis, offering valuable guidance for future studies focused JNK-targeting effective
Язык: Английский
Процитировано
0
Pharmaceuticals, Год журнала: 2025, Номер 18(2), С. 233 - 233
Опубликована: Фев. 8, 2025
Background/Objectives: Glioblastoma multiforme (GBM), an aggressive and deadly brain tumour, presents significant challenges in achieving effective treatment due to its resistance current therapies poor prognosis. This study aimed synthesise evaluate 23 novel analogues of 3,4-dihydroquinolin-2(1H)-one, designed enhance druggability solubility, investigate their potential as VEGFR2 inhibitors for GBM treatment. Methods: The synthesised compounds were analysed using silico methods, including molecular docking dynamics studies, assess interactions with key residues within the binding pocket. In vitro evaluations performed on U87-MG U138-MG cell lines MTT assays determine IC50 values compounds. Results: Among tested compounds, 4u (IC50 = 7.96 μM), 4t 10.48 4m 4.20 4q 8.00 μM) demonstrated antiproliferative effects against both lines. These exhibited markedly higher efficacy compared temozolomide (TMZ), which showed 92.90 μM 93.09 U138-MG, respectively. Molecular studies confirmed strong between kinase, supporting substantial anti-cancer activity. Conclusions: highlights promising 3,4-dihydroquinolin-2(1H)-one analogues, particularly 4m, 4q, 4t, 4u, VEGFR2-targeting therapeutic agents Further detailed research is warranted validate expand upon these findings.
Язык: Английский
Процитировано
0
eLife, Год журнала: 2025, Номер 13
Опубликована: Фев. 11, 2025
Excessive consumption of sucrose, in the form sugar-sweetened beverages, has been implicated pathogenesis metabolic dysfunction‐associated fatty liver disease (MAFLD) and other related syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role response to dietary stressors, it was demonstrated that inhibition JNK could potentially be used treatment MAFLD. However, intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water investigated potential by employing network analysis based on transcriptome profiling obtained from hepatic extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, brain. Our data demonstrate JNK-IN-5A effectively reduces circulating triglyceride accumulation inflammation subjected sucrose consumption. Coexpression genome-scale modeling reveal overconsumption primarily induces transcriptional dysfunction acid oxidative metabolism which are largely rectified after at clinically relevant dose. Skeletal muscle exhibited minimal changes but underwent substantial adaptation following inhibition. Overall, our provides novel insights into molecular basis exerts its effect metabolically active Furthermore, findings underpin critical development diet-induced steatosis, offering valuable guidance for future studies focused JNK-targeting effective
Язык: Английский
Процитировано
0
eLife, Год журнала: 2024, Номер unknown
Опубликована: Сен. 12, 2024
Excessive consumption of sucrose, in the form sugar-sweetened beverages, has been implicated pathogenesis metabolic dysfunctionLassociated fatty liver disease (MAFLD) and other related syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role response to dietary stressors, it was demonstrated that inhibition JNK could potentially be used treatment MAFLD. However, intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water investigated potential by employing network analysis based on transcriptome profiling obtained from hepatic extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, brain. Our data demonstrate JNK-IN-5A effectively reduces circulating triglyceride accumulation inflammation subjected sucrose consumption. Coexpression genome-scale modelling reveal overconsumption primarily induces transcriptional dysfunction acid oxidative metabolism which are largely rectified after at clinically relevant dose. Skeletal muscle exhibited minimal changes but underwent substantial adaptation following inhibition. Overall, our provides novel insights into molecular basis exerts its effect metabolically active Furthermore, findings underpin critical development diet-induced steatosis, offering valuable guidance for future studies focused JNK-targeting effective
Язык: Английский
Процитировано
2
Biomedicines, Год журнала: 2024, Номер 12(10), С. 2237 - 2237
Опубликована: Окт. 1, 2024
: Despite current treatments extending the lifespan of Glioblastoma (GBM) patients, average survival time is around 15-18 months, underscoring fatality GBM. This study aims to investigate impact sample heterogeneity on gene expression in GBM, identify key metabolic pathways and modules, explore potential therapeutic targets.
Язык: Английский
Процитировано
1
Biomolecules, Год журнала: 2024, Номер 14(11), С. 1376 - 1376
Опубликована: Окт. 29, 2024
Collagen VI-related dystrophies (COL6RD) are a group of rare muscle disorders caused by mutations in specific genes responsible for type VI collagen production. It affects muscles, joints, and connective tissues, leading to weakness, joint problems, structural issues. Currently, there is no effective treatment COL6RD; its management typically addresses symptoms complications. Therefore, it essential decipher the disease’s molecular mechanisms, identify drug targets, develop strategies treat COL6RD. In this study, we employed differential gene expression analysis, weighted co-expression network genome-scale metabolic modeling investigate patterns COL6RD patients, uncovering key genes, significant metabolites, disease-related pathophysiological pathways. First, performed analyses, which led identification 12 (CHCHD10, MRPS24, TRIP10, RNF123, MRPS15, NDUFB4, COX10, FUNDC2, MDH2, RPL3L, NDUFB11, PARVB) as potential hub involved disease. Second, utilized repurposing strategy pharmaceutical candidates that could potentially modulate these be treatment. Next, context-specific models compare variations between healthy individuals patients. Finally, conducted reporter metabolite analysis metabolites (e.g., phosphatidates, nicotinate ribonucleotide, ubiquinol, ferricytochrome C). summary, our revealed critical pathways associated with identified candidate drugs therapeutic interventions.
Язык: Английский
Процитировано
0
Elsevier eBooks, Год журнала: 2024, Номер unknown
Опубликована: Янв. 1, 2024
Язык: Английский
Процитировано
0
Current Opinion in Biotechnology, Год журнала: 2024, Номер 91, С. 103248 - 103248
Опубликована: Дек. 31, 2024
Язык: Английский
Процитировано
0