Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 53 - 75
Опубликована: Ноя. 1, 2024
Язык: Английский
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(16), С. 9082 - 9082
Опубликована: Авг. 21, 2024
Kynurenic acid (KYNA) is an antioxidant degradation product of tryptophan that has been shown to have a variety cytoprotective, neuroprotective and neuronal signalling properties. However, mammalian transporters receptors display micromolar binding constants; these are consistent with its typically tissue concentrations but far above serum/plasma concentration (normally tens nanomolar), suggesting large gaps in our knowledge transport mechanisms action, the main influx characterized date equilibrative, not concentrative. In addition, it substrate known anion efflux pump (ABCC4), whose vivo activity largely unknown. Exogeneous addition L-tryptophan or L-kynurenine leads production KYNA also many other co-metabolites (including some such as 3-hydroxy-L-kynurenine quinolinic may be toxic). With exception chestnut honey, exists at relatively low levels natural foodstuffs. bioavailability reasonable, terminal element irreversible reaction most pathways, might added exogenously without disturbing upstream metabolism significantly. Many examples, which we review, show valuable bioactivity. Given above, review potential utility nutraceutical, finding significantly worthy further study development.
Язык: Английский
Процитировано
6
Membranes, Год журнала: 2024, Номер 14(3), С. 70 - 70
Опубликована: Март 20, 2024
Transport systems play a pivotal role in bacterial physiology and represent potential targets for medical biotechnological applications. However, even well-studied organisms like Escherichia coli, notable proportion of transporters, exceeding as many 30%, remain classified orphans due to their lack known substrates. This study leveraged high-resolution LC-MS-based untargeted metabolomics identify candidate substrates these orphan transporters. Human serum, including diverse array biologically relevant molecules, served an unbiased source substrate exposure. The analysis encompassed 26 paired transporter mutant contrasts (i.e., knockout vs. overexpression), compared with the wild type, revealing distinct patterns uptake excretion across various mutants. convergence scenarios provided robust validation, shedding light on novel transporter-substrate relationships, those involving yeaV, hsrA, ydjE, yddA. Furthermore, several were contingent upon specific mutants employed. investigation underscores utility identification absence prior knowledge lays groundwork subsequent validation experiments, holding significant implications both advancements.
Язык: Английский
Процитировано
5
Molecular Biology of the Cell, Год журнала: 2025, Номер 36(2)
Опубликована: Янв. 28, 2025
The cellular electrical signals of living organisms were discovered more than a century ago and have been extensively investigated in the neuromuscular system. Neuronal depolarization hyperpolarization are essential for our physiological pathological functions. Bioelectricity is being recognized as an ancient, intrinsic, fundamental property all cells, it not limited to Instead, emerging evidence supports view bioelectricity instructional signaling cue physiology, embryonic development, regeneration, human diseases, including cancers. Here, we highlight current understanding share views on challenges perspectives.
Язык: Английский
Процитировано
0
BMC Genomics, Год журнала: 2025, Номер 26(1)
Опубликована: Фев. 11, 2025
Abstract Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, pharmacology, around one third SLC ‘orphans’ whose substrates unknown. Experimental determination is technically challenging, given the range possible physiological candidates. Here, we develop predictive algorithm to identify correlations between expression levels intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity specificity compared simulated random pairs. CRISPR-Cas9 dependency screen data metabolic pathway adjacency further improved performance our algorithm. In parallel, combined drug profiles predict new SLC-drug interactions. Together, provide novel bioinformatic pipeline substrate SLCs, offering opportunities de-orphanise SLCs important implications understanding their health disease.
Язык: Английский
Процитировано
0
BJC Reports, Год журнала: 2025, Номер 3(1)
Опубликована: Фев. 27, 2025
Abstract Most cancer-related deaths result from drug-resistant disease(1,2). However, cancer drug resistance is not a primary focus in development. Effectively mitigating and treating will require advancements multiple fields, including early detection, discovery, our fundamental understanding of biology. Therefore, successfully tackling requires an increasingly multidisciplinary approach. A recent workshop on resistance, jointly organised by Cancer Research UK, the Rosetrees Trust, UKRI-funded Physics Life Network, brought together experts cell biology, physical sciences, computational clinicians to these key challenges devise interdisciplinary approaches address them. In this perspective, we review outcomes highlight unanswered research questions. We outline emerging hallmarks discuss lessons COVID-19 pandemic antimicrobial that could help accelerate information sharing timely adoption discoveries into clinic. envisage initiatives drive greater interdisciplinarity yield rich dividends developing new ways better detect, monitor, treat thereby improving treatment for patients.
Язык: Английский
Процитировано
0
Frontiers in Genetics, Год журнала: 2025, Номер 16
Опубликована: Март 28, 2025
Transgenic mice and gene expression in analyses were employed to evaluate hazardous chemicals. Mice received weekly doses of NDEA (75 mg/kg) for six weeks twice-weekly BHT (300 eight weeks. Gene splicing alterations the livers transgenic each treatment examined using MouseExon10ST array. Six hybridizations revealed 645 genes with significant changes, 181 showed both (p < 0.01). Furthermore, 2021 demonstrated exon-group interactions, indicating potential alternative splicing. Pathway analysis identified enriched groups GOMolFn, GOProcess, GOCellLoc, classes, a higher representation alternatively spliced expressed Among top was TAT, which encodes mitochondrial enzyme tyrosine aminotransferase, involved metabolism recognized as novel tumor suppressor linked hepatocellular carcinoma (HCC). Additionally, HNF-4, transcription factor, plays crucial role TAT expression. This method can be used identify genotoxic compounds att-myc model short-term toxicity.
Язык: Английский
Процитировано
0
Frontiers in Pharmacology, Год журнала: 2025, Номер 16
Опубликована: Апрель 3, 2025
Background Non-small cell lung cancer (NSCLC) is one of the most prevalent and deadly malignancies worldwide. In previous studies, indacaterol, a drug used to manage chronic obstructive pulmonary disease, has shown antitumor activity. However, its role in context NSCLC remains underexplored. This study aimed investigate indacaterol’s mechanisms potential therapeutic effects treatment. Methods Expression profiles clinical information from TCGA database were analyzed explore impact SLC2A1 gene on progression NSCLC. The expression levels GLUT1 protein, encoded by gene, MCT4 SLC16A3 both normal tissues. Techniques such as cellular thermal shift assay (CETSA), immunofluorescence, Western blotting employed assess interaction between indacaterol GLUT1. Immunohistochemistry was human lines observed through wound healing colony formation assays. Additionally, animal experiments combined with PD-L1 inhibitors conducted evaluate vitro vivo . Results Analysis data revealed that promoting may work concert MCT4. Indacaterol significantly inhibited viability cells concentration-dependent manner. Molecular modeling CETSA further indicated bind affect expression. suggested also reduces MCT4, suggesting diminish capacity tumors reprogram stromal metabolism. confirmed combination synergistically proliferation invasion cells. Conclusion Indacaterol, inhibitor GLUT1, significant Moreover, immune checkpoint enhanced inhibitory Our provides scientific evidence supporting application novel strategy for
Язык: Английский
Процитировано
0
Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)
Опубликована: Ноя. 7, 2024
Solute carrier family 38 member 5 (SLC38A5) is an amino acid transporter that plays a significant role in various cellular biological processes and may be involved regulating the progression of tumors However, its function underlying mechanism osteosarcoma remain unexplored.
Язык: Английский
Процитировано
2
Опубликована: Июль 1, 2024
Aquaporins (AQPs) are a family of integral membrane proteins that selectively transport water and glycerol across the cell membrane. Because AQPs involved in wide range physiological functions pathophysiological conditions, AQP-based therapeutics may have broad potential for clinical utility, including disorders energy balance. However, AQP modulators not yet been developed as suitable candidates applications. In this study, to identify AQPs, we screened 32 natural products by measuring permeability mouse erythrocyte membranes using stopped-flow light scattering method. None tested compounds substantially affected osmotic permeability. several considerably Stichoposide C increased membranes, whereas rhizochalin decreased it at nanomolar concentrations. Immunohistochemistry revealed AQP7 was main aquaglyceroporin membranes. We further verified effects stichoposide on aquaglyceroporins human AQP3 expressing keratinocyte cells. C, but D, AQP3-mediated transepithelial transport, peracetyl aglycon most potent inhibitor among derivatives. Collectively, might function AQP7, suggest possibility these drug
Язык: Английский
Процитировано
1
Pharmacological Reviews, Год журнала: 2024, Номер 77(1), С. 100014 - 100014
Опубликована: Окт. 15, 2024
Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy oncology has so far been based primarily on characteristics, e.g., somatic mutations. However, the response to drug treatment also depends pharmacological processes summarized under term ADME (absorption, distribution, metabolism, excretion). Variations genes have subject of intensive research more than five decades, considering individual patients9 genetic makeup, referred as pharmacogenomics (PGx). The combined impact a patient9s germline genome only partially understood often not adequately considered therapy. This may be attributed, part, lack methods analysis both data layers. Optimized personalized therapies should, therefore, aim integrate molecular information about germline, taking into account existing PGx guidelines Moreover, such strategies should provide opportunity consider variants previously unknown functional significance. Bioinformatic corresponding algorithms interpretation need developed interdisciplinary boards, where patients discussed evidence-based recommendations clinical management profiles. Significance Statement era seen emergence tailored associated with biology. full potential therapy remains untapped due predominant focus acquired tumor-specific alterations. care must patient genomes, guided by pharmacogenomic principles. An essential prerequisite realizing truly development bioinformatic tools comprehensive all layers generated modern precision programs.
Язык: Английский
Процитировано
1