Published: Jan. 1, 2024
Language: Английский
Biochemistry, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 10, 2025
Proteolysis-targeting chimeras (PROTACs) represent a transformative advancement in drug discovery, offering method to degrade specific intracellular proteins. Unlike traditional inhibitors, PROTACs are bifunctional molecules that target proteins for elimination, enabling the potential treatment of previously "undruggable" This concept, pioneered by Crews and his team, introduced use small link protein an E3 ubiquitin ligase, inducing ubiquitination subsequent degradation protein. By promoting rather than merely inhibiting function, present novel therapeutic strategy with enhanced specificity effectiveness, especially areas such as cancer neurodegenerative diseases. Since their initial field PROTAC research has rapidly expanded numerous now designed wide range disease-relevant The substantial research, investment, collaboration across academia pharmaceutical industry reflect growing interest PROTACs. Review discusses journey from discovery clinical trials, highlighting advancements challenges. Additionally, recent developments fluorescent photogenic PROTACs, used real-time tracking degradation, presented, showcasing evolving targeted therapy.
Language: Английский
Citations
3
Matrix Biology, Journal Year: 2024, Volume and Issue: unknown
Published: Jan. 1, 2024
Language: Английский
Citations
9
Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15
Published: April 4, 2024
Immunotherapy has been developed, which harnesses and enhances the innate powers of immune system to fight disease, particularly cancer. PD-1 (programmed death-1) PD-L1 death ligand-1) are key components in regulation system, context cancer immunotherapy. regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation glycosylation. PROTACs (Proteolysis Targeting Chimeras) a type new drug design technology. They specifically engineered molecules that target specific proteins within cell for degradation. have designed demonstrated their inhibitory activity against PD-1/PD-L1 pathway, showed ability degrade proteins. In this review, we describe how improve efficacy could be novel strategy combine with radiotherapy, chemotherapy immunotherapy patients.
Language: Английский
Citations
6
Frontiers in Bioscience-Landmark, Journal Year: 2024, Volume and Issue: 29(8)
Published: Aug. 21, 2024
Background: Alzheimer’s disease (AD) is a neurodegenerative that remains serious global health issue. Ferroptosis has been recognized as vital driver of pathological progression AD. However, the detailed regulatory mechanisms ferroptosis during AD remain unclear. This study aimed to explore role and mechanism methyltransferase like 14 (METTL14) in models. Methods: Serum samples were collected from 18 patients healthy volunteers evaluate clinical correlation. Scopolamine-treated mice Aβ1–42-stimulated SH-SY5Y cells served vivo vitro models was detected by reactive oxygen species (ROS), Fe2+, total iron levels, ferroptosis-related proteins glutathione peroxidase 4 (GPX4) solute carrier family 7 member 11 (SLC7A11). Cell viability analyzed 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The N6-methyladenosine (m6A) modification RNA methylation quantification kit methylated immunoprecipitation sequencing-quantitative real-time polymerase chain reaction (MeRIP-qPCR). Molecular investigated pull-down, (RIP), co-immunoprecipitation (Co-IP) assays. Cognitive disorder measured Morris water maze test. Results: METTL14 down-regulated, while lncRNA taurine upregulated gene 1 (TUG1) up-regulated experimental Functional experiments demonstrated overexpression or TUG1 silencing effectively attenuated Aβ1–42-induced neurotoxicity cells. Mechanistically, METTL14-mediated m6A reduced stability TUG1. Moreover, promoted ubiquitination degradation growth differentiation factor 15 (GDF15) directly interacted with Smad ubiquitin (SMURF1), which consequently inactivated nuclear erythroid 2-related 2 (NRF2). Rescue indicated GDF15 depletion reversed sh-TUG1-mediated protection against neurotoxicity. Finally, Mettl14 repressed ameliorate cognitive via modulating Tug1/Gdf15/Nrf2 pathway vivo. Conclusion: inhibited development activate GDF15/NRF2 axis, providing novel therapeutic target for
Language: Английский
Citations
5
Journal of Controlled Release, Journal Year: 2025, Volume and Issue: 381, P. 113578 - 113578
Published: Feb. 26, 2025
Language: Английский
Citations
0
Molecular & Cellular Proteomics, Journal Year: 2025, Volume and Issue: unknown, P. 100942 - 100942
Published: March 1, 2025
Maternal-embryo interactions play a critical role in early mammalian development, with extracellular vesicles (EVs) playing key intercellular communication. Recent studies have focused on the mechanisms by which maternal-derived factors, such as RNA, proteins, and metabolites influence gap junctions, EVs, direct cell-to-cell interactions, contributing to embryonic development. In this study, using proteomics approach, we investigated impact of EVs secreted from porcine endometrial cells (pEECs) their protein cargoes We characterized isolated pEECs (pEEC-EVs) during diestrus stage nanoparticle tracking analysis cryo-transmission electron microscopy. Furthermore, effects pEEC-EVs or without hormone treatment vitro attachment hatched blastocysts were evaluated. The rate embryos was significantly higher for group than control (23.0 ± 1.7% vs. 36.9 1.9% pEEC-EVs, respectively). altered expression proteins involved cellular organization, transport, immunity. Proteomic revealed distinct biological processes between groups: supported cytoskeletal organization adhesion, while hormone-treated enriched immune regulation, stress response pathways. Key signaling pathways, including VEGFA-VEGFR2, focal TGF-β, modulated, influencing implantation embryogenesis. crucial maternal-embryo optimizing conditions supporting embryo-derived stem cell establishment. These findings enhance our understanding EV-mediated communication suggest potential applications improving reproductive health assisted technologies.
Language: Английский
Citations
0
Journal of Virology, Journal Year: 2025, Volume and Issue: unknown
Published: March 31, 2025
ABSTRACT African swine fever virus (ASFV) is a large double-stranded DNA virus, which the causative agent of (ASF), devastating disease suids epidemic in many countries. The has developed multiple strategies to evade surveillance from host immune system. Inflammatory responses, especially NF- κ B signaling pathway, play central roles ASFV pathogenesis and immunoevasion. In this study, we identified S273R protein (pS273R) as an antagonist canonical pathway independently its protease activity. ectopically expressed pS273R markedly inhibited tumor necrosis factor-alpha or interleukin-1 beta-triggered HEK293T PK-15 cells. Silencing by RNA interference led elevated expression levels proinflammatory cytokines ASFV-infected primary porcine alveolar macrophages. Mechanistically, functioned was associated with complex interrupted translocation I α into proteasome, resulting increased stability subsequently impaired nuclear p65. Furthermore, core domain (amino acids 83–273) essential for pS273R-mediated inhibition pathway. These findings demonstrate immunosuppressive role provide novel insights biological characteristics. IMPORTANCE (ASF) hemorrhagic caused (ASFV), morbidity mortality rates up 100%. significant economic losses global industry. identify Our pS273R, will contribute better understanding may development antiviral therapies against ASF.
Language: Английский
Citations
0
Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108453 - 108453
Published: April 1, 2025
Language: Английский
Citations
0
Foods, Journal Year: 2025, Volume and Issue: 14(9), P. 1559 - 1559
Published: April 29, 2025
Neurodegenerative disorders such as Alzheimer's disease (AD), the most common form of dementia, represent a growing global health crisis, yet current treatment strategies remain primarily palliative. Recent studies have shown that neurodegeneration through complex interactions within gut-brain axis largely depends on gut microbiota and its metabolites. This review explores intricate molecular mechanisms linking dysbiosis to cognitive decline, emphasizing impact microbial metabolites, including short-chain fatty acids (SCFAs), bile acids, tryptophan neuroinflammation, blood-brain barrier (BBB) integrity, amyloid-β tau pathology. The paper highlights major microbiome signatures associated with disease, detailing their metabolic pathways inflammatory crosstalk. Dietary interventions promise in modulating composition, potentially mitigating neurodegenerative processes. critically examines influence dietary patterns, Mediterranean Western diets, microbiota-mediated neuroprotection. Bioactive compounds like prebiotics, omega-3 polyphenols exhibit neuroprotective effects by reducing neuroinflammation. Furthermore, it discusses emerging microbiome-based therapeutic strategies, probiotics, postbiotics, fecal transplantation (FMT), potential for slowing progression. Despite these advances, several knowledge gaps remain, interindividual variability responses need large-scale, longitudinal studies. study proposes an integrative, precision medicine approach, incorporating science into paradigms. Ultimately, cognizance at mechanistic level could unlock novel avenues, offering non-invasive, diet-based strategy managing improving health.
Language: Английский
Citations
0
Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)
Published: April 29, 2025
Language: Английский
Citations
0