International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 139483 - 139483
Опубликована: Янв. 1, 2025
Язык: Английский
Nature Reviews Gastroenterology & Hepatology, Год журнала: 2022, Номер 19(7), С. 432 - 450
Опубликована: Фев. 14, 2022
Язык: Английский
Процитировано
263
Pharmaceutics, Год журнала: 2022, Номер 14(6), С. 1283 - 1283
Опубликована: Июнь 16, 2022
The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a for syphilis, salvarsan, did not enter brain, due to presence blood–brain barrier (BBB). Owing restricted transport across BBB, FDA-approved drugs CNS have been generally limited lipid-soluble small molecules. Drugs do cross BBB can be re-engineered on endogenous carrier-mediated and receptor-mediated systems, which were identified during 1970s–1980s. By 1990s, multitude technologies emerged, including trans-cranial delivery, CSF disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, biologics. advantages limitations each these are critically reviewed.
Язык: Английский
Процитировано
140
Frontiers in Immunology, Год журнала: 2021, Номер 12
Опубликована: Апрель 19, 2021
Cancer cells are metabolically vigorous and superior in the uptake of nutrients release tumor microenvironment (TME)-specific metabolites. They create an acidic, hypoxic, nutrient-depleted TME that makes it difficult for cytotoxic immune to adapt hostile environment. Since a robust metabolism is required optimal anti-tumor effector functions, challenges caused by result severe defects invasion destruction established tumors. There have been many recent developments NK T cell-mediated immunotherapy, such as engineering them express chimeric antigen receptors (CARs) enhance tumor-recognition infiltration. However, defeat overcome limitations TME, essential fortify these novel therapies improving cells. One potential strategy metabolic fitness upregulate expression nutrient transporters, specifically glucose amino acid transporters. In particular, transporters SLC1A5 SLC7A5 well ancillary subunit SLC3A2, which efficient glutamine leucine respectively, could strengthen capabilities functions tumor-directed CAR-NK addition enabling influx efflux acids through plasma membrane within subcellular compartments lysosome mitochondria, accumulating evidence has demonstrated participate sensing levels thereby activate mTORC1, master regulator promotes cell metabolism, induce c-Myc, transcription factor growth proliferation. this review, we discuss regulatory pathways how can take advantage processes immunotherapy against cancer.
Язык: Английский
Процитировано
114
Nature Metabolism, Год журнала: 2022, Номер 4(10), С. 1232 - 1244
Опубликована: Окт. 20, 2022
Язык: Английский
Процитировано
81
Nature, Год журнала: 2024, Номер 626(8001), С. 963 - 974
Опубликована: Фев. 28, 2024
Язык: Английский
Процитировано
29
Nature Immunology, Год журнала: 2024, Номер 25(12), С. 2297 - 2307
Опубликована: Ноя. 8, 2024
Abstract CD8 + T cells are critical mediators of antitumor immunity but differentiate into a dysfunctional state, known as cell exhaustion, after persistent receptor stimulation in the tumor microenvironment (TME). Exhausted (T ex ) characterized by upregulation coinhibitory molecules and reduced polyfunctionality. TME experience an immunosuppressive metabolic environment via levels nutrients oxygen buildup lactic acid. Here we show that terminally uniquely upregulate Slc16a11 , which encodes monocarboxylate transporter 11 (MCT11). Conditional deletion MCT11 acid uptake improved their effector function. Targeting with antibody lactate specifically cells, which, when used therapeutically tumor-bearing mice, resulted growth. These data support model MCT11, rendering them sensitive to present at high TME.
Язык: Английский
Процитировано
27
Cell chemical biology, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce selective protein degradation by linking an E3 ubiquitin ligase enzyme to a target protein. This approach allows scope for "undruggable" proteins, and several PROTACs have reached the stage of clinical candidates. However, roles cellular transmembrane transporters in PROTAC uptake efflux remain underexplored. Here, we utilized transporter-focused genetic screens identify ATP-binding cassette transporter ABCC1/MRP1 as key resistance factor. Unlike previously identified inducible exporter ABCB1/MDR1, ABCC1 is highly expressed among cancers various origins constitutively restricts bioavailability. Moreover, genome-wide screen, candidates involved processes such ubiquitination, mTOR signaling, apoptosis factors resistance. In summary, our findings reveal crucial active pump limiting efficacy cancer cells, offering insights overcoming drug
Язык: Английский
Процитировано
4
Molecular Systems Biology, Год журнала: 2025, Номер unknown
Опубликована: Май 12, 2025
Abstract The human solute carrier (SLC) superfamily of ~460 membrane transporters remains the largest understudied protein family despite its therapeutic potential. To advance SLC research, we developed a comprehensive knowledgebase that integrates systematic multi-omics data sets with selected curated information from public sources. We annotated substrates through literature curation, compiled disease associations using mining techniques, and determined subcellular localization SLCs by combining annotations databases an immunofluorescence imaging approach. This SLC-centric knowledge is made accessible to scientific community via web portal featuring interactive dashboards visualization tools. Utilizing this systematically collected resource, computationally derived integrated functional landscape for entire superfamily. identified clusters distinct properties established distances between transporters. Based on all available their integration, assigned biochemical/biological functions each SLC, making study one gene function potential blueprint future research endeavors.
Язык: Английский
Процитировано
4
Molecular Systems Biology, Год журнала: 2025, Номер unknown
Опубликована: Май 12, 2025
Abstract Solute carrier (SLC) transporters govern most of the chemical exchange across cellular membranes and are integral to metabolic regulation, which in turn is linked function identity. Despite their key role, individual functions SLC superfamily members were not evaluated systematically. We determined transcriptional profiles upon overexpression knock-out or wild-type isogenic cell backgrounds for 378 SLCs 441 SLCs, respectively. Targeted metabolomics provided a fingerprint 189 intracellular metabolites, while transcriptomics offered insights into programs modulated by expression. Beyond 102 directly related known substrates, we identified putative substrates pathway connections 71 without previously annotated bona fide including SLC45A4 as new polyamine transporter. By comparing molecular profiles, functionally groups, some with distinct impacts on osmolyte balancing glycosylation. The assessment human genes presented here may serve blueprint other systematic studies supports future investigations functional roles SLCs.
Язык: Английский
Процитировано
4
Molecular Systems Biology, Год журнала: 2025, Номер unknown
Опубликована: Май 12, 2025
Abstract Solute carrier (SLC) transporters form a protein superfamily that enables transmembrane transport of diverse substrates including nutrients, ions and drugs. There are about 450 different SLCs, residing in variety subcellular membranes. Loss-of-function an unusually high proportion SLC is genetically associated with plethora human diseases, making SLCs rapidly emerging but challenging drug target class. Knowledge their environment may elucidate the molecular basis for functional integration metabolic cellular pathways help conceive pharmacological interventions based on modulating proteostatic regulation. We aimed at obtaining global survey SLC-protein interaction landscape mapped protein–protein interactions 396 by proteomics. employed assessment RNA interference interactors combination measurement stability localization. As example, we detail role SLC16A6 phospho-degron contributions PDZ-domain proteins LIN7C MPP1 to trafficking SLC43A2. Overall, our work offers resource scientific community.
Язык: Английский
Процитировано
4