Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN - including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology - without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.
Introduction: The plasma membrane-bound protein, multi-drug resistance-associated protein 4 (), has gained attention for its pivotal role in facilitating the efflux of a wide range of endogenous and xenobiotic molecules. Its significance in adipogenesis and fatty acid metabolism has been brought to light by recent studies. Notably, research on knockout ( ) mice has established a link between the absence of and the development of obesity and diabetes.
With the global implementation of wastewater reuse, accurately assessing the soil ecological risk of chiral pollutants from wastewater necessitates a comprehensive understanding of their enantioselective toxicity to soil animals. Ibuprofen (IBU) is the most prevalent chiral pharmaceutical in municipal wastewater. However, its enantioselective toxicity toward soil animals and the underlying mechanism remain largely unknown.
The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China; Shanghai Key Laboratory of Birth Defect, Shanghai 201102, China. Electronic address:
Background: Ubiquitin-specific protease 53 (USP53) deficiency is associated with familial intrahepatic cholestasis in which serum gamma-glutamyl transferase (GGT) activity is relatively low. However, how USP53 deficiency contributes to cholestasis is obscure. No animal model has been reported.
This study investigates the transcriptional profile of a novel oil-degrading microbial consortium (MC1) composed of four bacterial isolates from Brazilian oil reservoirs: Acinetobacter baumannii subsp. oleum ficedula, Bacillus velezensis, Enterobacter asburiae, and Klebsiella pneumoniae. Genomic analysis revealed an enrichment of genes associated with xenobiotic degradation, particularly for aminobenzoate, atrazine, and aromatic compounds, compared to reference genomes.
Microplastics represent a threat due to their ability to enter the food chain, with harmful consequences for living organisms. The riskiness of these particles is also linked to the release of other contaminants, such as heavy metals. Solute Carriers (SLCs) represent eminent examples of first-level targets of heavy metals due to their localization on the cell surface.
